Substituted aminopiperidines as dipeptidyl peptidase-IV inhibitors for the treatment of diabetes

ABSTRACT

The present invention is directed to novel substituted aminopiperidines of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-ÏV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/US2010/048871, filed Sep. 15, 2010,which published as WO 2011/037793 A1 on Mar. 31, 2011, and claimspriority under 35 U.S.C. §365(b) from U.S. patent application No.61/245,704, filed Sep. 25, 2009.

FIELD OF THE INVENTION

The present invention relates to novel substituted aminopiperidineswhich are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-4inhibitors”) and which are useful in the treatment of diseases in whichthe dipeptidyl peptidase-IV enzyme is involved, such as diabetes andparticularly Type 2 diabetes. The invention is also directed topharmaceutical compositions comprising these compounds and the use ofthese compounds and compositions in the treatment of such diseases inwhich the dipeptidyl peptidase-IV enzyme is involved.

BACKGROUND OF THE INVENTION

Diabetes refers to a disease process derived from multiple causativefactors and characterized by elevated levels of plasma glucose orhyperglycemia in the fasting state or after administration of glucoseduring an oral glucose tolerance test. Persistent or uncontrolledhyperglycemia is associated with increased and premature morbidity andmortality. Often abnormal glucose homeostasis is associated bothdirectly and indirectly with alterations of the lipid, lipoprotein andapolipoprotein metabolism and other metabolic and hemodynamic disease.Therefore patients with Type 2 diabetes mellitus are at especiallyincreased risk of macrovascular and microvascular complications,including coronary heart disease, stroke, peripheral vascular disease,hypertension, nephropathy, neuropathy, and retinopathy. Therefore,therapeutical control of glucose homeostasis, lipid metabolism andhypertension are critically important in the clinical management andtreatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In Type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), patientsproduce little or no insulin, the hormone which regulates glucoseutilization. In Type 2 diabetes, or noninsulin dependent diabetesmellitus (NIDDM), patients often have plasma insulin levels that are thesame or even elevated compared to nondiabetic subjects; however, thesepatients have developed a resistance to the insulin stimulating effecton glucose and lipid metabolism in the main insulin-sensitive tissues,which are muscle, liver and adipose tissues, and the plasma insulinlevels, while elevated, are insufficient to overcome the pronouncedinsulin resistance.

Insulin resistance is not primarily due to a diminished number ofinsulin receptors but to a post-insulin receptor binding defect that isnot yet understood. This resistance to insulin responsiveness results ininsufficient insulin activation of glucose uptake, oxidation and storagein muscle and inadequate insulin repression of lipolysis in adiposetissue and of glucose production and secretion in the liver.

The available treatments for Type 2 diabetes, which have not changedsubstantially in many years, have recognized limitations. While physicalexercise and reductions in dietary intake of calories will dramaticallyimprove the diabetic condition, compliance with this treatment is verypoor because of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of saturatedfat. Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, whichstimulate the pancreatic β cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinide becomeineffective, can result in insulin concentrations high enough tostimulate the very insulin-resistant tissues. However, dangerously lowlevels of plasma glucose can result from administration of insulin orinsulin secretagogues (sulfonylureas or meglitinide), and an increasedlevel of insulin resistance due to the even higher plasma insulin levelscan occur. The biguanides increase insulin sensitivity resulting in somecorrection of hyperglycemia. However, the two biguanides, phenformin andmetformin, can induce lactic acidosis and nausea/diarrhea. Metformin hasfewer side effects than phenformin and is often prescribed for thetreatment of Type 2 diabetes.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) constitute anadditional class of compounds with potential for ameliorating manysymptoms of Type 2 diabetes. These agents substantially increase insulinsensitivity in muscle, liver and adipose tissue in several animal modelsof Type 2 diabetes resulting in partial or complete correction of theelevated plasma levels of glucose without occurrence of hypoglycemia.The glitazones that are currently marketed are agonists of theperoxisome proliferator activated receptor (PPAR), primarily thePPAR-gamma subtype. PPAR-gamma agonism is generally believed to beresponsible for the improved insulin sensititization that is observedwith the glitazones. Newer PPAR agonists that are being tested fortreatment of Type 2 diabetes are agonists of the alpha, gamma or deltasubtype, or a combination of these, and in many cases are chemicallydifferent from the glitazones (i.e., they are not thiazolidinediones instructure). Serious side effects (e.g. liver toxicity) have occurredwith some of the glitazones, such as troglitazone.

Additional methods of treating the disease are still underinvestigation. New biochemical approaches that have been recentlyintroduced or are still under development include alpha-glucosidaseinhibitors (e.g. acarbose), GLP-1 mimetics (eg., exenatide andliraglutide), glucagon receptor antagonists, glucokinase activators, andGPR-119 agonists.

Compounds that are inhibitors of the dipeptidyl peptidase-IV (“DPP-4”)enzyme have also been found useful for the treatment of diabetes,particularly Type 2 diabetes [See WO 97/40832; WO 98/19998; U.S. Pat.Nos. 5,939,560; 6,303,661; 6,699,871; 6,166,063; Bioorg. Med. Chem.Lett., 6: 1163-1166 (1996); Bioorg. Med. Chem. Lett., 6: 2745-2748(1996); D. J. Drucker in Exp. Opin. Invest. Drugs, 12: 87-100 (2003); K.Augustyns, et al., Exp. Opin. Ther. Patents, 13: 499-510 (2003); Ann E.Weber, J. Med. Chem., 47: 4135-4141 (2004); J. J. Holst, Exp. Opin.Emerg. Drugs, 9: 155-166 (2004); D. Kim, et al., J. Med. Chem., 48:141-151 (2005); K. Augustyns, Exp. Opin. Ther. Patents, 15: 1387-1407(2005); H.-U. Demuth in Biochim. Biophys. Acta, 1751: 33-44 (2005); andR. Mentlein, Exp. Opin. Invest. Drugs, 14: 57-64 (2005).

Additional patent publications that disclose DPP-4 inhibitors useful forthe treatment of diabetes are the following: WO 2006/009886 (26 Jan.2006); WO 2006/039325 (13 Apr. 2006); WO 2006/058064 (1 Jun. 2006); WO2006/127530 (30 Nov. 2006); WO 2007/024993 (1 Mar. 2007); WO 2007/070434(21 Jun. 2007); WO 2007/087231 (2 Aug. 2007); WO 07/097,931 (30 Aug.2007); WO 07/126,745 (8 Nov. 2007); WO 07/136,603 (29 Nov. 2007); and WO08/060,488 (22 May 2008).

The usefulness of DPP-4 inhibitors in the treatment of Type 2 diabetesis based on the fact that DPP-4 in vivo readily inactivates glucagonlike peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 andGIP are incretins and are produced when food is consumed. The incretinsstimulate production of insulin. Inhibition of DPP-4 leads to decreasedinactivation of the incretins, and this in turn results in increasedeffectiveness of the incretins in stimulating production of insulin bythe pancreas. DPP-4 inhibition therefore results in an increased levelof serum insulin. Advantageously, since the incretins are produced bythe body only when food is consumed, DPP-4 inhibition is not expected toincrease the level of insulin at inappropriate times, such as betweenmeals, which can lead to excessively low blood sugar (hypoglycemia).Inhibition of DPP-4 is therefore expected to increase insulin withoutincreasing the risk of hypoglycemia, which is a dangerous side effectassociated with the use of insulin secretagogues.

DPP-4 inhibitors also have other therapeutic utilities, as discussedherein. New compounds are needed so that improved DPP-4 inhibitors canbe found for the treatment of diabetes and potentially other diseasesand conditions. In particular, there is a need for DPP-4 inhibitors thatare selective over other members of the family of serine peptidases thatincludes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9 [seeG. Lankas, et al., “Dipeptidyl Peptidase-IV Inhibition for the Treatmentof Type 2 Diabetes: Potential Importance of Selectivity Over DipeptidylPeptidases 8 and 9,” Diabetes, 54: 2988-2994 (2005); N. S. Kang, et al.,“Docking-based 3D-QSAR study for selectivity of DPP4, DPP8, and DPP9inhibitors,” Bioorg. Med. Chem. Lett., 17: 3716-3721 (2007)].

The therapeutic potential of DPP-4 inhibitors for the treatment of Type2 diabetes is discussed by (i) D. J. Drucker, Exp. Opin. Invest. Drugs,12: 87-100 (2003); (ii) K. Augustyns, et al., Exp. Opin. Ther. Patents,13: 499-510 (2003); (iii) J. J. Holst, Exp. Opin. Emerg. Drugs, 9:155-166 (2004); (iv) H.-U. Demuth, et al., Biochim. Biophys. Acta, 1751:33-44 (2005); (v) R. Mentlein, Exp. Opin. Invest. Drugs, 14: 57-64(2005); (vi) K. Augustyns, “Inhibitors of proline-specific dipeptidylpeptidases: DPP IV inhibitors as a novel approach for the treatment ofType 2 diabetes,” Exp. Opin. Ther. Patents, 15: 1387-1407 (2005); (vii)D. J. Drucker and M. A. Nauck, “The incretin system: GLP-1 receptoragonists and dipeptidyl peptidase-4 inhibitors in Type 2 diabetes,” TheLancet, 368: 1696-1705 (2006); (viii) T. W. von Geldern and J. M.Trevillyan, ““The Next Big Thing” in Diabetes: Clinical Progress onDPP-IV Inhibitors,” Drug Dev. Res., 67: 627-642 (2006); (ix) B. D. Greenet al., “Inhibition of dipeptidyl peptidase IV activity as a therapy ofType 2 diabetes,” Exp. Opin. Emerging Drugs, 11: 525-539 (2006); (x) J.J. Holst and C. F. Deacon, “New Horizons in Diabetes Therapy,” Immun.,Endoc. & Metab. Agents in Med. Chem., 7: 49-55 (2007); (xi) R. K.Campbell, “Rationale for Dipeptidyl Peptidase 4 Inhibitors: a New Classof Oral Agents for the Treatment of Type 2 Diabetes Mellitus,” Ann.Pharmacother., 41: 51-60 (2007); (xii) Z. Pei, “From the bench to thebedside: Dipeptidyl peptidase IV inhibitors, a new class of oralantihyperglycemic agents,” Curr. Opin. Drug Discovery Development, 11:512-532 (2008); and (xiii) J. J. Holst, et al., “Glucagon-likepeptide-1, glucose homeostasis, and diabetes, Trends in MolecularMedicine, 14: 161-168 (2008). Specific DPP-4 inhibitors either alreadyapproved or under clinical investigation for the treatment of Type 2diabetes include sitagliptin, vildagliptin, saxagliptin, alogliptin,carmegliptin, melogliptin, and dutogliptin.

SUMMARY OF THE INVENTION

The present invention is directed to novel substituted3-aminopiperidines which are inhibitors of the dipeptidyl peptidase-IVenzyme (“DPP-4 inhibitors”) and which are useful in the treatment ofdiseases in which the dipeptidyl peptidase-IV enzyme is involved, suchas diabetes and particularly Type 2 diabetes. The invention is alsodirected to pharmaceutical compositions comprising these compounds andthe use of these compounds and compositions in the treatment of suchdiseases in which the dipeptidyl peptidase-IV enzyme is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel substituted 3-aminopiperidinesthat are useful as inhibitors of dipeptidyl peptidase-IV. Compounds ofthe present invention are described by structural formula I:

and pharmaceutically acceptable salts thereof; wherein

-   V is selected from the group consisting of:

-   Ar is phenyl optionally substituted with one to five R¹    substituents;-   each R¹ is independently selected from the group consisting of:    -   halogen,    -   cyano,    -   hydroxy,    -   C₁₋₆ alkyl, optionally substituted with one to five fluorines,        and    -   C₁₋₆ alkoxy, optionally substituted with one to five fluorines;-   each R² is independently selected from the group consisting of    hydrogen, halogen, cyano, and C₁₋₄ alkyl optionally substituted with    one to five fluorines;-   R^(3a) and R^(3b) are each independently hydrogen or C₁₋₄ alkyl    optionally substituted with one to five fluorines;-   R^(a) is selected from the group consisting of:    -   hydrogen,    -   —C₁₋₆ alkyl, wherein alkyl is optionally substituted with one to        five substituents independently selected from CO₂H, cyano,        deuterium, fluorine, hydroxy, and C₁₋₄ alkoxycarbonyl,    -   —C₁₋₄ alkylcarbonyl, wherein the alkyl moiety is optionally        substituted with one to five fluorines,    -   —C(═O)CH₂aryl, wherein aryl is optionally substituted with one        to five substituents independently selected hydroxy, halogen,        cyano, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₄ alkylsulfonyl,        C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are        optionally substituted with one to five fluorines,    -   —C(═O)CH₂heteroaryl, wherein heteroaryl is optionally        substituted with one to five substituents independently selected        hydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl,        C₁₋₄ alkylsulfonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl        and alkoxy are optionally substituted with one to five        fluorines,    -   (CH₂)_(n)-aryl, wherein aryl is optionally substituted with one        to five substituents independently selected hydroxy, halogen,        cyano, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₄ alkylsulfonyl,        C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are        optionally substituted with one to five fluorines,    -   (CH₂)_(n)-heteroaryl, wherein heteroaryl is optionally        substituted with one to three substituents independently        selected from hydroxy, halogen, cyano, pyrrolidin-1-yl,        morpholin-1-yl, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₄        alkylsulfonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are optionally substituted with one to five fluorines,    -   (CH₂)_(n)—N-heteroaryl, wherein heteroaryl is optionally        substituted with one to three substituents independently        selected from hydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆        alkyloxycarbonyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkyl, and C₁₋₆        alkoxy, wherein alkyl and alkoxy are optionally substituted with        one to five fluorines,    -   (CH₂)_(n)-heterocyclyl, wherein heterocyclyl is optionally        substituted with one to three substituents independently        selected from oxo, hydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆        alkyloxycarbonyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkyl, and C₁₋₆        alkoxy, wherein alkyl and alkoxy are optionally substituted with        one to five fluorines,    -   (CH₂)_(m)—C₃₋₆ cycloalkyl, wherein cycloalkyl is optionally        substituted with one to three substituents independently        selected from halogen, hydroxy, cyano, nitro, CO₂H, C₁₋₆        alkyloxycarbonyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkyl, and C₁₋₆        alkoxy, wherein alkyl and alkoxy are optionally substituted with        one to five fluorines,    -   (CH₂)_(n)—COOH,    -   (CH₂)_(n)—COOC₁₋₆ alkyl,    -   (CH₂)_(n)—NR⁴R⁵,    -   (CH₂)_(n)—CONR⁴R⁵,    -   (CH₂)_(n)—OCONR⁴R⁵,    -   (CH₂)_(m)—SO₂NR⁴R⁵,    -   (CH₂)_(n)—SO₂R⁶,    -   (CH₂)_(n)—NR⁷SO₂R⁶,    -   (CH₂)_(n)—NR⁷CONR⁴R⁵,    -   (CH₂)_(n)—NR⁷COR⁷, and    -   (CH₂)_(n)—NR⁷CO₂R⁶;-   wherein any individual methylene (CH₂) carbon atom in (CH₂)_(n) is    optionally substituted with one to two substituents independently    selected from fluorine, hydroxy, C₁₋₄ alkyl, and C₁₋₄ alkoxy,    wherein alkyl and alkoxy are optionally substituted with one to five    fluorines;-   R⁴ and R⁵ are each independently selected from the group consisting    of hydrogen,    -   (CH₂)_(m)-phenyl,    -   (CH₂)_(m)-heteroaryl,    -   (CH₂)_(m)-heterocyclyl,    -   (CH₂)_(m)—C₃₋₆ cycloalkyl, and    -   C₁₋₆ alkyl, wherein alkyl is optionally substituted with one to        five substituents independently selected from fluorine and        hydroxy and wherein phenyl, heteroaryl, heterocyclyl, and        cycloalkyl are optionally substituted with one to five        substituents independently selected from halogen, hydroxy, C₁₋₆        alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are optionally        substituted with one to five fluorines;-   or R⁴ and R⁵ together with the nitrogen atom to which they are    attached form a heterocyclic ring selected from azetidine,    pyrrolidine, piperidine, piperazine, and morpholine wherein said    heterocyclic ring is optionally substituted with one to three    substituents independently selected from halogen, hydroxy, C₁₋₆    alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are optionally    substituted with one to five fluorines; and wherein said    heterocyclic ring is optionally fused with a five or six-membered    heteroaryl group containing one to three heteroatoms selected from    oxygen, sulfur, and nitrogen, said fused heterocyclic ring being    optionally substituted with one to two substituents independently    selected from halogen and C₁₋₄ alkyl optionally substituted with one    to five fluorines;-   R⁸ is selected from the group consisting of:    -   hydrogen,    -   C₁₋₆ alkyl, wherein alkyl is optionally substituted with hydroxy        or one to five fluorines,    -   (CH₂)_(p)-phenyl, wherein phenyl is optionally substituted with        one to five substituents independently selected from halogen,        hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy        are optionally substituted with one to five fluorines,    -   (CH₂)_(p)—C₃₋₆ cycloalkyl, wherein cycloalkyl is optionally        substituted with one to five substituents independently selected        from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein        alkyl and alkoxy are optionally substituted with one to five        fluorines,    -   —SO₂C₁₋₆ alkyl,    -   —SO₂C₃₋₆ cycloalkyl,    -   —SO₂-aryl,    -   —SO₂-heteroaryl,    -   —C(O)C₁₋₆ alkyl,    -   —C(O)C₃₋₆ cycloalkyl,    -   —C(O)-aryl,    -   —C(O)-heteroaryl,    -   —C(O)OC₁₋₆ alkyl,    -   —C(O)OC₃₋₆ cycloalkyl,    -   —C(O)O-aryl,    -   —C(O)O-heteroaryl,    -   —C(O)NHC₁₋₆ alkyl,    -   —C(O)NHC₃₋₆ cycloalkyl,    -   —C(O)NH-aryl, and    -   —C(O)NH-heteroaryl;-   wherein alkyl and cycloalkyl are optionally substituted with one to    five fluorines and wherein aryl and heteroaryl are optionally    substituted with one to five substituents independently selected    from the group consisting of hydroxy, halogen, cyano, nitro, CO₂H,    C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl    and alkoxy are optionally substituted with one to five fluorines;-   each R⁶ is independently C₁₋₆ alkyl, wherein alkyl is optionally    substituted with one to five substituents independently selected    from fluorine and hydroxyl;-   R⁷ is hydrogen or R⁶;-   p is an integer selected from 0 and 1;-   each n is an integer independently selected from 1, 2 and 3; and-   each m is an integer independently selected from 0, 1, and 2.

In one embodiment of the compounds of the present invention, Ar isoptionally substituted with one to three substituents independentlyselected from the group consisting of fluorine, chlorine, bromine,methyl, trifluoromethyl, and trifluoromethoxy. In a class of thisembodiment, Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl.

In a second embodiment of the compounds of the present invention, R^(3a)and R^(3b) are both hydrogen.

In a third embodiment of the compounds of the present invention, V isselected from the group consisting of:

wherein R² and R⁸ are as defined above. In a class of this embodiment,R² is hydrogen.In another class of this third embodiment, V is

In a subclass of this class, R² is hydrogen.

In a fourth embodiment of the compounds of the present invention, R⁸ isselected from the group consisting of:

-   -   hydrogen,    -   C₁₋₆ alkyl, wherein alkyl is optionally substituted with hydroxy        or one to five fluorines,    -   —SO₂C₁₋₆ alkyl, and    -   —SO₂C₃₋₆ cycloalkyl,        wherein alkyl and cycloalkyl are optionally substituted with one        to five fluorines. In a class of this embodiment, R⁸ is selected        from the group consisting of hydrogen, —SO₂C₁₋₃ alkyl, and        —SO₂cyclopropyl.

In a fifth embodiment of the compounds of the present invention, thereare provided compounds of structural formulae Ia and Ib of the indicatedstereochemical configuration having a trans orientation of the Ar andNH₂ substituents on the two stereogenic tetrahydropyran carbon atomsmarked with an *:

wherein Ar and V are as described above.

In a class of this fifth embodiment, there are provided compounds ofstructural formula Ia of the indicated absolute stereochemicalconfiguration having a trans orientation of the Ar and NH₂ substituentson the two stereogenic tetrahydropyran carbon atoms marked with an *:

In a second class of this fifth embodiment, there are provided compoundsof structural formulae Ic and Id of the indicated stereochemicalconfiguration having a trans orientation of the Ar and NH₂ substituents,a trans orientation of the Ar and V substituents and a cis orientationof the NH₂ and V substituents on the three stereogenic tetrahydropyrancarbon atoms marked with an *:

In a subclass of this class, there are provided compounds of structuralformula Ic of the indicated absolute stereochemical configuration havinga trans orientation of the Ar and NH₂ substituents, a trans orientationof the Ar and V substituents and a cis orientation of the NH₂ and Vsubstituents on the three stereogenic tetrahydropyran carbon atomsmarked with an *:

In a subclass of this subclass, V is selected from the group consistingof:

wherein R² and R⁸ are as defined above. In a subclass of this secondsubclass, R² is hydrogen, and R⁸ is selected from the group consistingof hydrogen, —SO₂C₁₋₃ alkyl, and —SO₂cyclopropyl.

In a third class of this fifth embodiment, there are provided compoundsof structural formulae Ie and If of the indicated stereochemicalconfiguration having a trans orientation of the Ar and NH₂ substituents,a cis orientation of the Ar and V substituents and a trans orientationof the NH₂ and V substituents on the three stereogenic tetrahydropyrancarbon atoms marked with an *:

In a subclass of this class, there are provided compounds of structuralformula Ie of the indicated absolute stereochemical configuration havinga trans orientation of the Ar and NH₂ substituents, a cis orientation ofthe Ar and V substituents and a trans orientation of the NH₂ and Vsubstituents on the three stereogenic tetrahydropyran carbon atomsmarked with an *:

In a subclass of this subclass, V is selected from the group consistingof:

wherein R² and R⁸ are as defined above. In a subclass of this secondsubclass, R² is hydrogen, and R⁸ is selected from the group consistingof hydrogen, —SO₂C₁₋₃ alkyl, and —SO₂cyclopropyl.

In a sixth embodiment of the compounds of the present invention, each R²is independently selected from the group consisting of hydrogen;

-   -   cyano;    -   C₁₋₆ alkyl, wherein alkyl is optionally substituted with hydroxy        or one to five fluorines; and    -   C₃₋₆ cycloalkyl, wherein cycloalkyl is optionally substituted        with one to three substituents independently selected from        halogen, hydroxy, C₁₋₄ alkyl, and C₁₋₄ alkoxy, wherein alkyl and        alkoxy are optionally substituted with one to five fluorines.

In a class of this sixth embodiment of the compounds of the presentinvention, each R² is independently selected from the group consistingof hydrogen, cyano, C₁₋₃ alkyl, trifluoromethyl, 2,2,2-trifluoroethyl,and cyclopropyl. In a subclass of this class, each R² is hydrogen.

Nonlimiting examples of compounds of the present invention that areuseful as dipeptidyl peptidase-IV inhibitors are the followingstructures having the indicated absolute stereochemical configurationsat the three stereogenic tetrahydropyran carbon atoms:

IC₅₀ DPP-4 Example Inhibition

 6.8 nM

 0.7 nM

 4.3 nM

 1.0 nM

 0.9 nM

14.5 nM

 1.7 nM

 1.6 nM

 0.4 nM

25.4 nM

 7.1 nM

12.9 nM

 3.0 nM

 2.9 nM

53.3 nM

 3.9 nM

24.6 nMand pharmaceutically acceptable salts thereof.

As used herein the following definitions are applicable.

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxyand alkanoyl, means carbon chains which may be linear or branched, andcombinations thereof, unless the carbon chain is defined otherwise.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and thelike. Where the specified number of carbon atoms permits, e.g., fromC₃₋₁₀, the term alkyl also includes cycloalkyl groups, and combinationsof linear or branched alkyl chains combined with cycloalkyl structures.When no number of carbon atoms is specified, C₁₋₆ is intended.

“Cycloalkyl” is a subset of alkyl and means a saturated carbocyclic ringhaving a specified number of carbon atoms. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and the like. A cycloalkyl group generally is monocyclicunless stated otherwise. Cycloalkyl groups are saturated unlessotherwise defined.

The term “alkoxy” refers to straight or branched chain alkoxides of thenumber of carbon atoms specified (e.g., C₁₋₁₀ alkoxy), or any numberwithin this range [i.e., methoxy (MeO—), ethoxy, isopropoxy, etc.].

The term “alkylthio” refers to straight or branched chain alkylsulfidesof the number of carbon atoms specified (e.g., C₁₋₁₀ alkylthio), or anynumber within this range [i.e., methylthio (MeS—), ethylthio,isopropylthio, etc.]

The term “alkylamino” refers to straight or branched alkylamines of thenumber of carbon atoms specified (e.g., C₁₋₆ alkylamino), or any numberwithin this range [i.e., methylamino, ethylamino, isopropylamino,t-butylamino, etc.].

The term “alkylsulfonyl” refers to straight or branched chainalkylsulfones of the number of carbon atoms specified (e.g., C₁₋₆alkylsulfonyl), or any number within this range [i.e., methylsulfonyl(MeSO₂—), ethylsulfonyl, isopropylsulfonyl, etc.].

The term “alkyloxycarbonyl” refers to straight or branched chain estersof a carboxylic acid derivative of the present invention of the numberof carbon atoms specified (e.g., C₁₋₆ alkyloxycarbonyl), or any numberwithin this range [i.e., methyloxycarbonyl (MeOCO—), ethyloxycarbonyl,or butyloxycarbonyl].

“Aryl” means a mono- or polycyclic aromatic ring system containingcarbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.The most preferred aryl is phenyl.

The term “heterocyclyl” refers to saturated or unsaturated non-aromaticrings or ring systems containing at least one heteroatom selected fromO, S and N, further including the oxidized forms of sulfur, namely SOand SO₂. Examples of heterocycles include tetrahydrofuran (THF),dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine,piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline,pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane,1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, pyrrolidinone,oxazolidin-2-one, imidazolidine-2-one, pyridone, and the like.

“Heteroaryl” means an aromatic or partially aromatic heterocycle thatcontains at least one ring heteroatom selected from O, S and N.Heteroaryls also include heteroaryls fused to other kinds of rings, suchas aryls, cycloalkyls and heterocycles that are not aromatic. Examplesof heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl,pyrazolyl, pyridinyl, 2-oxo-(1H)-pyridinyl (2-hydroxy-pyridinyl),oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl,pyrimidinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl,indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl,phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl,quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl,benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl,dibenzofuranyl, imidazo[1,2-a]pyridinyl,[1,2,4-triazolo][4,3-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4-triazolo][1,5-a]pyridinyl, 2-oxo-1,3-benzoxazolyl,4-oxo-3H-quinazolinyl, 3-oxo-[1,2,4]-triazolo[4,3-a]-2H-pyridinyl,5-oxo-[1,2,4]-4H-oxadiazolyl, 2-oxo-[1,3,4]-3H-oxadiazolyl,2-oxo-1,3-dihydro-2H-imidazolyl, 3-oxo-2,4-dihydro-3H-1,2,4-triazolyl,and the like. For heterocyclyl and heteroaryl groups, rings and ringsystems containing from 3-15 atoms are included, forming 1-3 rings.

“Halogen” refers to fluorine, chlorine, bromine and iodine. Chlorine andfluorine are generally preferred. Fluorine is most preferred when thehalogens are substituted on an alkyl or alkoxy group (e.g. CF₃O andCF₃CH₂O).

The compounds of the present invention contain one or more asymmetriccenters and can thus occur as racemates, racemic mixtures, singleenantiomers, diastereomeric mixtures, and individual diastereomers. Inparticular the compounds of the present invention have an asymmetriccenter at the stereogenic carbon atoms marked with an * in formulae Ia,Ib, Ic, Id, Ie, and If. Additional asymmetric centers may be presentdepending upon the nature of the various substituents on the molecule.Each such asymmetric center will independently produce two opticalisomers and it is intended that all of the possible optical isomers anddiastereomers in mixtures and as pure or partially purified compoundsare included within the ambit of this invention. The present inventionis meant to comprehend all such isomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers, whichhave different points of attachment of hydrogen accompanied by one ormore double bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of the present invention. Anexample of tautomers which are intended to be encompassed within thecompounds of the present invention is illustrated below:

Formula I shows the structure of the class of compounds withoutpreferred stereochemistry. Formulae Ia and Ib show the preferredstereochemistry at the stereogenic carbon atoms to which are attachedthe NH₂ and Ar groups on the tetrahydropyran ring. Formulae Ic and Idshow the preferred stereochemistry at the stereogenic carbon atoms towhich are attached the NH₂, Ar, and V groups on the tetrahydropyranring.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the X-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

In the compounds of generic Formula I, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofgeneric Formula I. For example, different isotopic forms of hydrogen (H)include protium (¹H) and deuterium (²H). Protium is the predominanthydrogen isotope found in nature. Enriching for deuterium may affordcertain therapeutic advantages, such as increasing in vivo half-life orreducing dosage requirements, or may provide a compound useful as astandard for characterization of biological samples.Isotopically-enriched compounds within generic Formula I can be preparedwithout undue experimentation by conventional techniques well known tothose skilled in the art or by processes analogous to those described inthe Schemes and Examples herein using appropriate isotopically-enrichedreagents and/or intermediates.

It will be understood that, as used herein, references to the compoundsof structural formula I are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof include, butare not limited to, salts derived from inorganic bases includingaluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.Particularly preferred are the ammonium, calcium, magnesium, potassium,and sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, cyclic amines, and basic ion-exchange resins, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included arethose esters and acyl groups known in the art for modifying thesolubility or hydrolysis characteristics for use as sustained-release orprodrug formulations.

Solvates, and in particular, the hydrates of the compounds of structuralformula I are included in the present invention as well.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein.

The subject compounds are useful in a method of inhibiting thedipeptidyl peptidase-IV enzyme in a patient such as a mammal in need ofsuch inhibition comprising the administration of an effective amount ofthe compound. The present invention is directed to the use of thecompounds disclosed herein as inhibitors of dipeptidyl peptidase-IVenzyme activity.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species(e.g., chickens).

The present invention is further directed to a method for themanufacture of a medicament for inhibiting dipeptidyl peptidase-IVenzyme activity in humans and animals comprising combining a compound ofthe present invention with a pharmaceutically acceptable carrier ordiluent. More particularly, the present invention is directed to the useof a compound of structural formula I in the manufacture of a medicamentfor use in treating a condition selected from the group consisting ofhyperglycemia, Type 2 diabetes, obesity, and a lipid disorder in amammal, wherein the lipid disorder is selected from the group consistingof dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, and high LDL.

The subject treated in the present methods is generally a mammal,preferably a human being, male or female, in whom inhibition ofdipeptidyl peptidase-IV enzyme activity is desired. The term“therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asinhibitors of dipeptidyl peptidase-IV enzyme activity may bedemonstrated by methodology known in the art. Inhibition constants aredetermined as follows. A continuous fluorometric assay is employed withthe substrate Gly-Pro-AMC, which is cleaved by DPP-4 to release thefluorescent AMC leaving group. The kinetic parameters that describe thisreaction are as follows: K_(m)=50 μM; k_(cat)=75 s⁻¹;k_(cat)/K_(m)=1.5×10⁶ M⁻¹s⁻¹. A typical reaction contains approximately50 μM enzyme, 50 μM Gly-Pro-AMC, and buffer (100 mM HEPES, pH 7.5, 0.1mg/ml BSA) in a total reaction volume of 100 μL. Liberation of AMC ismonitored continuously in a 96-well plate fluorometer using anexcitation wavelength of 360 nm and an emission wavelength of 460 nm.Under these conditions, approximately 0.8 μM AMC is produced in 30minutes at 25 degrees C. The enzyme used in these studies was soluble(transmembrane domain and cytoplasmic extension excluded) human proteinproduced in a baculovirus expression system (Bac-To-Bac, Gibco BRL). Thekinetic constants for hydrolysis of Gly-Pro-AMC and GLP-1 were found tobe in accord with literature values for the native enzyme. To measurethe dissociation constants for compounds, solutions of inhibitor in DMSOwere added to reactions containing enzyme and substrate (final DMSOconcentration is 1%). All experiments were conducted at room temperatureusing the standard reaction conditions described above. To determine thedissociation constants (K_(i)), reaction rates were fit by non-linearregression to the Michaelis-Menton equation for competitive inhibition.The errors in reproducing the dissociation constants are typically lessthan two-fold.

The compounds of structural formula (I), particularly the specificExamples shown below, had activity in inhibiting the dipeptidylpeptidase-IV enzyme in the aforementioned assays, generally with an IC₅₀of less than about 1 μM, and more typically of less than 0.1 μM. Suchresults are indicative of the intrinsic activity of the compounds of thepresent invention for use as inhibitors the dipeptidyl peptidase-IVenzyme activity.

Dipeptidyl peptidase-IV enzyme (DPP-4) is a cell surface protein thathas been implicated in a wide range of biological functions. It has abroad tissue distribution (intestine, kidney, liver, pancreas, placenta,thymus, spleen, epithelial cells, vascular endothelium, lymphoid andmyeloid cells, serum), and distinct tissue and cell-type expressionlevels. DPP-4 is identical to the T cell activation marker CD26, and itcan cleave a number of immunoregulatory, endocrine, and neurologicalpeptides in vitro. This has suggested a potential role for thispeptidase in a variety of disease processes in humans or other species.

Accordingly, the subject compounds are useful in a method for theprevention or treatment of the following diseases, disorders andconditions.

-   Type II Diabetes and Related Disorders: It is well established that    the incretins GLP-1 and GIP are rapidly inactivated in vivo by    DPP-4. Studies with DPP-4^((−/−))-deficient mice and preliminary    clinical trials indicate that DPP-4 inhibition increases the steady    state concentrations of GLP-1 and GIP, resulting in improved glucose    tolerance. By analogy to GLP-1 and GIP, it is likely that other    glucagon family peptides involved in glucose regulation are also    inactivated by DPP-4 (eg. PACAP). Inactivation of these peptides by    DPP-4 may also play a role in glucose homeostasis. The DPP-4    inhibitors of the present invention therefore have utility in the    treatment of type II diabetes and in the treatment and prevention of    the numerous conditions that often accompany Type II diabetes,    including Syndrome X (also known as Metabolic Syndrome), reactive    hypoglycemia, and diabetic dyslipidemia. Obesity, discussed below,    is another condition that is often found with Type II diabetes that    may respond to treatment with the compounds of this invention.

The following diseases, disorders and conditions are related to Type 2diabetes, and therefore may be treated, controlled or in some casesprevented, by treatment with the compounds of this invention: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), and other disorderswhere insulin resistance is a component. In Syndrome X, also known asMetabolic Syndrome, obesity is thought to promote insulin resistance,diabetes, dyslipidemia, hypertension, and increased cardiovascular risk.Therefore, DPP-4 inhibitors may also be useful to treat hypertensionassociated with this condition.

-   Obesity: DPP-4 inhibitors may be useful for the treatment of    obesity. This is based on the observed inhibitory effects on food    intake and gastric emptying of GLP-1 and GLP-2. Exogenous    administration of GLP-1 in humans significantly decreases food    intake and slows gastric emptying (Am. J. Physiol., 277: R910-R916    (1999)). ICV administration of GLP-1 in rats and mice also has    profound effects on food intake (Nature Medicine, 2: 1254-1258    (1996)). This inhibition of feeding is not observed in    GLP-1R^((−/−)) mice, indicating that these effects are mediated    through brain GLP-1 receptors. By analogy to GLP-1, it is likely    that GLP-2 is also regulated by DPP-4. ICV administration of GLP-2    also inhibits food intake, analogous to the effects observed with    GLP-1 (Nature Medicine, 6: 802-807 (2000)). In addition, studies    with DPP-4 deficient mice suggest that these animals are resistant    to diet-induced obesity and associated pathology (e.g.    hyperinsulinonemia).-   Cardiovascular Disease: GLP-1 has been shown to be beneficial when    administered to patients following acute myocardial infarction,    leading to improved left ventricular function and reduced mortality    after primary angioplasty (Circulation, 109: 962-965 (2004)). GLP-1    administration is also useful for the treatment of left ventricular    systolic dysfunction in dogs with dilated cardiomyopathy and    ischemic induced left ventricular dysfunction, and thus may prove    useful for the treatment of patients with heart failure    (US2004/0097411). DPP-4 inhibitors are expected to show similar    effects through their ability to stabilize endogenous GLP-1.-   Growth Hormone Deficiency: DPP-4 inhibition may be useful for the    treatment of growth hormone deficiency, based on the hypothesis that    growth-hormone releasing factor (GRF), a peptide that stimulates    release of growth hormone from the anterior pituitary, is cleaved by    the DPP-4 enzyme in vivo (WO 00/56297). The following data provide    evidence that GRF is an endogenous substrate: (1) GRF is efficiently    cleaved in vitro to generate the inactive product GRF[3-44] (BBA    1122: 147-153 (1992)); (2) GRF is rapidly degraded in plasma to    GRF[3-44]; this is prevented by the DPP-4 inhibitor diprotin A;    and (3) GRF[3-44] is found in the plasma of a human GRF transgenic    pig (J. Clin. Invest., 83: 1533-1540 (1989)). Thus DPP-4 inhibitors    may be useful for the same spectrum of indications which have been    considered for growth hormone secretagogues.-   Intestinal Injury: The potential for using DPP-4 inhibitors for the    treatment of intestinal injury is suggested by the results of    studies indicating that glucagon-like peptide-2 (GLP-2), a likely    endogenous substrate for DPP-4, may exhibit trophic effects on the    intestinal epithelium (Regulatory Peptides, 90: 27-32 (2000)).    Administration of GLP-2 results in increased small bowel mass in    rodents and attenuates intestinal injury in rodent models of colitis    and enteritis.-   Immunosuppression: DPP-4 inhibition may be useful for modulation of    the immune response, based upon studies implicating the DPP-4 enzyme    in T cell activation and in chemokine processing, and efficacy of    DPP-4 inhibitors in in vivo models of disease. DPP-4 has been shown    to be identical to CD26, a cell surface marker for activated immune    cells. The expression of CD26 is regulated by the differentiation    and activation status of immune cells. It is generally accepted that    CD26 functions as a co-stimulatory molecule in in vitro models of T    cell activation. A number of chemokines contain praline in the    penultimate position, presumably to protect them from degradation by    non-specific aminopeptidases. Many of these have been shown to be    processed in vitro by DPP-4. In several cases (RANTES, LD78-beta,    MDC, eotaxin, SDF-1alpha), cleavage results in an altered activity    in chemotaxis and signaling assays. Receptor selectivity also    appears to be modified in some cases (RANTES). Multiple N-terminally    truncated forms of a number of chemokines have been identified in in    vitro cell culture systems, including the predicted products of    DPP-4 hydrolysis.

DPP-4 inhibitors have been shown to be efficacious immunosuppressants inanimal models of transplantation and arthritis. Prodipine(Pro-Pro-diphenyl-phosphonate), an irreversible inhibitor of DPP-4, wasshown to double cardiac allograft survival in rats from day 7 to day 14(Transplantation., 63: 1495-1500 (1997)). DPP-4 inhibitors have beentested in collagen and alkyldiamine-induced arthritis in rats and showeda statistically significant attenuation of hind paw swelling in thismodel [Int. J. Immunopharmacology., 19:15-24 (1997) andImmunopharmacology, 40: 21-26 (1998)]. DPP-4 is upregulated in a numberof autoimmune diseases including rheumatoid arthritis, multiplesclerosis, Graves' disease, and Hashimoto's thyroiditis (ImmunologyToday, 20: 367-375 (1999)).

-   HIV Infection: DPP-4 inhibition may be useful for the treatment or    prevention of HIV infection or AIDS because a number of chemokines    which inhibit HIV cell entry are potential substrates for DPP-4    (Immunology Today 20: 367-375 (1999)). In the case of SDF-1alpha,    cleavage decreases antiviral activity (PNAS, 95: 6331-6 (1998)).    Thus, stabilization of SDF-1alpha through inhibition of DPP-4 would    be expected to decrease HIV infectivity.-   Hematopoiesis: DPP-4 inhibition may be useful for the treatment or    prevention of hematopiesis because DPP-4 may be involved in    hematopoiesis. A DPP-4 inhibitor, Val-Boro-Pro, stimulated    hematopoiesis in a mouse model of cyclophosphamide-induced    neutropenia (WO 99/56753).-   Neuronal Disorders: DPP-4 inhibition may be useful for the treatment    or prevention of various neuronal or psychiatric disorders because a    number of peptides implicated in a variety of neuronal processes are    cleaved in vitro by DPP-4. A DPP-4 inhibitor thus may have a    therapeutic benefit in the treatment of neuronal disorders.    Endomorphin-2, beta-casomorphin, and substance P have all been shown    to be in vitro substrates for DPP-4. In all cases, in vitro cleavage    is highly efficient, with k_(cat)/K_(m) about 10⁶ M⁻¹s⁻¹ or greater.    In an electric shock jump test model of analgesia in rats, a DPP-4    inhibitor showed a significant effect that was independent of the    presence of exogenous endomorphin-2 (Brain Research, 815: 278-286    (1999)). Neuroprotective and neuroregenerative effects of DPP-4    inhibitors were also evidenced by the inhibitors' ability to protect    motor neurons from excitotoxic cell death, to protect striatal    innervation of dopaminergic neurons when administered concurrently    with MPTP, and to promote recovery of striatal innervation density    when given in a therapeutic manner following MPTP treatment [see    Yong-Q. Wu, et al., “Neuroprotective Effects of Inhibitors of    Dipeptidyl peptidase-IV In Vitro and In Vivo,” Int. Conf. On    Dipeptidyl Aminopeptidases: Basic Science and Clinical Applications,    Sep. 26-29, 2002 (Berlin, Germany)].-   Anxiety: Rats naturally deficient in DPP-4 have an anxiolytic    phenotype (WO 02/34243; Karl et al., Physiol. Behav. 2003). DPP-4    deficient mice also have an anxiolytic phenotype using the porsolt    and light/dark models. Thus DPP-4 inhibitors may prove useful for    treating anxiety and related disorders.-   Memory and Cognition: GLP-1 agonists are active in models of    learning (passive avoidance, Morris water maze) and neuronal injury    (kainate-induced neuronal apoptosis) as demonstrated by During et    al. (Nature Med. 9: 1173-1179 (2003)). The results suggest a    physiological role for GLP-1 in learning and neuroprotection.    Stabilization of GLP-1 by DPP-4 inhibitors are expected to show    similar effects-   Myocardial Infarction: GLP-1 has been shown to be beneficial when    administered to patients following acute myocardial infarction    (Circulation, 109: 962-965 (2004)). DPP-4 inhibitors are expected to    show similar effects through their ability to stabilize endogenous    GLP-1.-   Tumor Invasion and Metastasis: DPP-4 inhibition may be useful for    the treatment or prevention of tumor invasion and metastasis because    an increase or decrease in expression of several ectopeptidases    including DPP-4 has been observed during the transformation of    normal cells to a malignant phenotype (J. Exp. Med., 190: 301-305    (1999)). Up- or down-regulation of these proteins appears to be    tissue and cell-type specific. For example, increased CD26/DPP-4    expression has been observed on T cell lymphoma, T cell acute    lymphoblastic leukemia, cell-derived thyroid carcinomas, basal cell    carcinomas, and breast carcinomas. Thus, DPP-4 inhibitors may have    utility in the treatment of such carcinomas.-   Benign Prostatic Hypertrophy: DPP-4 inhibition may be useful for the    treatment of benign prostatic hypertrophy because increased DPP-4    activity was noted in prostate tissue from patients with BPH    (Eur. J. Clin. Chem. Clin. Biochem., 30: 333-338 (1992)).-   Sperm motility/male contraception: DPP-4 inhibition may be useful    for the altering sperm motility and for male contraception because    in seminal fluid, prostatosomes, prostate derived organelles    important for sperm motility, possess very high levels of DPP-4    activity (Eur. J. Clin. Chem. Clin. Biochem., 30: 333-338 (1992)).-   Gingivitis: DPP-4 inhibition may be useful for the treatment of    gingivitis because DPP-4 activity was found in gingival crevicular    fluid and in some studies correlated with periodontal disease    severity (Arch. Oral Biol., 37: 167-173 (1992)).-   Osteoporosis: DPP-4 inhibition may be useful for the treatment or    prevention of osteoporosis because GIP receptors are present in    osteoblasts.-   Stem Cell Transplantation: Inhibition of DPP-4 on donor stem cells    has been shown to lead to an enhancement of their bone marrow homing    efficiency and engraftment, and an increase in survival in mice    (Christopherson, et al., Science, 305:1000-1003 (2004)). Thus DPP-4    inhibitors may be useful in bone marrow transplantation.

The compounds of the present invention have utility in treating orpreventing one or more of the following conditions or diseases: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), (25) Type 2 diabetes,(26) growth hormone deficiency, (27) neutropenia, (28) neuronaldisorders, (29) tumor metastasis, (30) benign prostatic hypertrophy,(32) gingivitis, (33) hypertension, (34) osteoporosis, (35) anxiety,(36) memory deficit, (37) cognition deficit, (38) stroke, (39)Alzheimer's disease, and other conditions that may be treated orprevented by inhibition of DPP-4.

The compounds of the present invention are further useful in methods forthe prevention or treatment of the aforementioned diseases, disordersand conditions in combination with other therapeutic agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, suppression oramelioration of diseases or conditions for which compounds of Formula Ior the other drugs may have utility, where the combination of the drugstogether are safer or more effective than either drug alone. Such otherdrug(s) may be administered, by a route and in an amount commonly usedtherefor, contemporaneously or sequentially with a compound of FormulaI. When a compound of Formula I is used contemporaneously with one ormore other drugs, a pharmaceutical composition in unit dosage formcontaining such other drugs and the compound of Formula I is preferred,particularly in combination with a pharmaceutically acceptable carrier.However, the combination therapy may also include therapies in which thecompound of Formula I and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundsof the present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof Formula I.

When a compound of the present invention is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of the present invention ispreferred. Accordingly, the pharmaceutical compositions of the presentinvention include those that also contain one or more other activeingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Examples of other active ingredients that may be administered incombination with a compound of Formula I, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

-   -   (1) insulin sensitizers, including (i) PPARγ agonists, such as        the glitazones (e.g. pioglitazone, rosiglitazone, netoglitazone,        rivoglitazone, and balaglitazone) and other PPAR ligands,        including (1) PPARα/γ dual agonists, such as muraglitazar,        aleglitazar, sodelglitazar, and naveglitazar, (2) PPARα        agonists, such as fenofibric acid derivatives (gemfibrozil,        clofibrate, ciprofibrate, fenofibrate and bezafibrate), (3)        selective PPARγ modulators (SPPARγM's), such as those disclosed        in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO        2004/020408, and WO 2004/066963, and (4) PPARγ, partial        agonists; (ii) biguanides, such as metformin and its        pharmaceutically acceptable salts, in particular, metformin        hydrochloride, and extended-release formulations thereof, such        as Glumetza®, Fortamet®, and GlucophageXR®; (iii) protein        tyrosine phosphatase-1B (PTP-1B) inhibitors;    -   (2) insulin and insulin analogs or derivatives, such as insulin        lispro, insulin detemir, insulin glargine, insulin glulisine,        and inhalable formulations of each thereof;    -   (3) leptin and leptin derivatives, agonists, and analogs, such        as metreleptin;    -   (4) amylin; amylin analogs, such as davalintide; and amylin        agonists, such as pramlintide;    -   (5) sulfonylurea and non-sulfonylurea insulin secretagogues,        such as tolbutamide, glyburide, glipizide, glimepiride,        mitiglinide, and meglitinides, such as nateglinide and        repaglinide;    -   (6) α-glucosidase inhibitors (such as acarbose, voglibose and        miglitol);    -   (7) glucagon receptor antagonists, such as those disclosed in WO        98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;    -   (8) incretin mimetics, such as GLP-1, GLP-1 analogs,        derivatives, and mimetics (See for example, WO 2008/011446, U.S.        Pat. Nos. 5,545,618, 6,191,102, and US56583111); and GLP-1        receptor agonists, such as oxyntomodulin and its analogs and        derivatives (See for example, WO 2003/022304, WO 2006/134340, WO        2007/100535), glucagon and its analogs and derivatives (See for        example, WO 2008/101017), exenatide, liraglutide, taspoglutide,        albiglutide, AVE0010, CJC-1134-PC, NN9535, LY2189265, LY2428757,        and BIM-51077, including intranasal, transdermal, and        once-weekly formulations thereof, such as exenatide QW;    -   (9) LDL cholesterol lowering agents such as (i) C (lovastatin,        simvastatin, pravastatin, cerivastatin, fluvastatin,        atorvastatin, pitavastatin, and rosuvastatin), (ii) bile acid        sequestering agents (such as cholestyramine, colestimide,        colesevelam hydrochloride, colestipol, and dialkylaminoalkyl        derivatives of a cross-linked dextran, (iii) inhibitors of        cholesterol absorption, such as ezetimibe, and (iv) acyl        CoA:cholesterol acyltransferase inhibitors, such as avasimibe;    -   (10) HDL-raising drugs, such as niacin or a salt thereof and        extended-release versions thereof; MK-524A, which is a        combination of niacin extended-release and the DP-1 antagonist        MK-524; and nicotinic acid receptor agonists;    -   (11) antiobesity compounds;    -   (12) agents intended for use in inflammatory conditions, such as        aspirin, non-steroidal anti-inflammatory drugs (NSAIDs),        glucocorticoids, and selective cyclooxygenase-2 (COX-2)        inhibitors;    -   (13) antihypertensive agents, such as ACE inhibitors (such as        enalapril, lisinopril, ramipril, captopril, quinapril, and        tandolapril), A-II receptor blockers (such as losartan,        candesartan, irbesartan, olmesartan medoxomil, valsartan,        telmisartan, and eprosartan), renin inhibitors (such as        aliskiren), beta blockers (such as and calcium channel blockers        (such as;    -   (14) glucokinase activators (GKAs), such as LY2599506;    -   (15) inhibitors of 11β-hydroxysteroid dehydrogenase type 1, such        as those disclosed in U.S. Pat. No. 6,730,690; WO 03/104207; and        WO 04/058741;    -   (16) inhibitors of cholesteryl ester transfer protein (CETP),        such as torcetrapib and MK-0859;    -   (17) inhibitors of fructose 1,6-bisphosphatase, such as those        disclosed in U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748;        6,399,782; and 6,489,476;    -   (18) inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2);    -   (19) AMP-activated Protein Kinase (AMPK) activators;    -   (20) agonists of the G-protein-coupled receptors: GPR-109,        GPR-116, GPR-119, and GPR-40;    -   (21) SSTR3 antagonists, such as those disclosed in WO        2009/011836;    -   (22) neuromedin U receptor 1 (NMUR1) and/or neuromedin U        receptor 2 (NMUR2) agonists, such as those disclosed in        WO2007/109135 and WO2009/042053, including, but not limited to,        neuromedin U (NMU) and neuromedin S (NMS) and their analogs and        derivatives;    -   (23) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD);    -   (24) GPR-105 (P2YR14) antagonists, such as those disclosed in WO        2009/000087;    -   (25) inhibitors of glucose uptake, such as sodium-glucose        transporter (SGLT) inhibitors and its various isoforms, such as        SGLT-1; SGLT-2, such as dapagliflozin and remogliflozin; and        SGLT-3;    -   (26) inhibitors of acyl coenzyme A: diacylglycerol        acyltransferase 1 and 2 (DGAT-1 and DGAT-2);    -   (27) inhibitors of fatty acid synthase;    -   (28) inhibitors of acyl coenzyme A: monoacylglycerol        acyltransferase 1 and 2 (MGAT-1 and MGAT-2);    -   (29) agonists of the TGR5 receptor (also known as GPBAR1, BG37,        GPCR19, GPR131, and M-BAR);    -   (30) bromocriptine mesylate and rapid-release formulations        thereof;    -   (31) histamine H3 receptor agonists; and    -   (32) α2-adrenergic or β3-adrenergic receptor agonists.

Antiobesity compounds that can be combined with compounds of Formula Iinclude topiramate; zonisamide; naltrexone; phentermine; bupropion; thecombination of bupropion and naltrexone; the combination of bupropionand zonisamide; the combination of topiramate and phentermine;fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such asorlistat and cetilistat; melanocortin receptor agonists, in particular,melanocortin-4 receptor agonists; CCK-1 agonists; melanin-concentratinghormone (MCH) receptor antagonists; neuropeptide Y₁ or Y₅ antagonists(such as MK-0557); CB1 receptor inverse agonists and antagonists (suchas rimonabant and taranabant); β₃ adrenergic receptor agonists; ghrelinantagonists; bombesin receptor agonists (such as bombesin receptorsubtype-3 agonists); histamine H3 receptor inverse agonists;5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin; andinhibitors of fatty acid synthase (FAS). For a review of anti-obesitycompounds that can be combined with compounds of the present invention,see S. Chaki et al., “Recent advances in feeding suppressing agents:potential therapeutic strategy for the treatment of obesity,” ExpertOpin. Ther. Patents, 11: 1677-1692 (2001); D. Spanswick and K. Lee,“Emerging antiobesity drugs,” Expert Opin. Emerging Drugs, 8: 217-237(2003); J. A. Fernandez-Lopez, et al., “Pharmacological Approaches forthe Treatment of Obesity,” Drugs, 62: 915-944 (2002); and K. M. Gadde,et al., “Combination pharmaceutical therapies for obesity,” Exp. Opin.Pharmacother., 10: 921-925 (2009).

Glucagon receptor antagonists that can be used in combination with thecompounds of Formula I include, but are not limited to:

-   N-[4-((1S)-1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol-1-yl}ethyl)benzoyl]-β-alanine;-   N-[4-(1R)-1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol-1-yl}ethyl)benzoyl]-β-alanine;-   N-(4-{1-[3-(2,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alanine;-   N-(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alanine;-   N-(4-{(1S)-1-[(R)-(4-chlorophenyl)(7-fluoro-5-methyl-1H-indol-3-yl)methyl]butyl}benzoyl)-β-alanine;    and-   N-(4-{(1S)-1-[(4-chlorophenyl)(6-chloro-8-methylquinolin-4-yl)methyl]butyl}benzoyl)-β-alanine;    and    pharmaceutically acceptable salts thereof.

Inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) that can beused in combination with the compounds of Formula I include, but are notlimited to:

-   [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetic    acid;-   (2′-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-2,5′-bi-1,3-thiazol-4-yl)acetic    acid;-   (5-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]isoxazol-5-yl}-2H-tetrazol-2-yl)acetic    acid;-   (3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyrrol-1-yl)acetic    acid;-   (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazin-2-yl}-2H-tetrazol-2-yl)acetic    acid; and-   (5-{2-[4-(5-bromo-2-chlorophenoxy)piperidin-1-yl]pyrimidin-5-yl}-2H-tetrazol-2-yl)acetic    acid; and    pharmaceutically acceptable salts thereof.

Glucokinase activators that can be used in combination with thecompounds of Formula I include, but are not limited to:

-   3-(6-methanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-({4-[2-(dimethylamino)ethoxy]phenyl}thio)-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide;-   3-({4-[(1-methylazetidin-3-yl)oxy]phenyl}thio)-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide;-   N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]thio}pyridine-2-carboxamide;    and-   3-[(4-{2-[(2R)-2-methylpyrrolidin-1-yl]ethoxy}phenyl)thio-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide;    and pharmaceutically acceptable salts thereof.

Agonists of the GPR-119 receptor that can be used in combination withthe compounds of Formula I include, but are not limited to:

-   rac-cis    5-chloro-2-{4-[2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy)ethyl}cyclopropyl]piperidin-1-yl}pyrimidine;-   5-chloro-2-{4-[(1R,2S)-2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine;-   rac    cis-5-chloro-2-[4-(2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine;-   5-chloro-2-[4-((1S,2R)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine;-   5-chloro-2-[4-((1R,2S)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine;-   rac    cis-5-chloro-2-[4-(2-{2-[3-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine;    and-   rac    cis-5-chloro-2-[4-(2-{2-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine;    and    pharmaceutically acceptable salts thereof.

Selective PPARγ modulators (SPPARγM's) that can be used in combinationwith the compounds of Formula I include, but are not limited to:

-   (2S)-2-({6-chloro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-yl]-1,2-benzisoxazol-5-yl}oxy)propanoic    acid;-   (2S)-2-({6-chloro-3-(6-(4-fluorophenoxy)-2-propylpyridin-3,2-benzisoxazol-5-yl}oxy)propanoic    acid;-   (2S)-2-{[6-chloro-3-(6-phenoxy-2-propylpyridin-3-yl)-1,2-benzisoxazol-5-yl]oxy}propanoic    acid;-   (2R)-2-({6-chloro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-yl]-1,2-benzisoxazol-5-yl}oxy)propanoic    acid;-   (2R)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoic    acid;-   (2S)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoic    acid;-   2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}-2-methylpropanoic    acid; and-   (2R)-2-{3-[3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic    acid; and    pharmaceutically acceptable salts thereof.

Inhibitors of 11β-hydroxysteroid dehydrogenase type 1 that can be usedin combination with the compounds of Formula I include, but are notlimited to:

-   3-[1-(4-chlorophenyl)-trans-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H-1,2,4-triazole;-   3-[1-(4-chlorophenyl)-trans-3-fluorocyclobutyl]-4-cyclopropyl-5-(1-methylcyclopropyl)-r-4H-1,2,4-triazole;-   3-[1-(4-chlorophenyl)-trans-3-fluorocyclobutyl]-4-methyl-5-[2-(trifluoromethoxy)phenyl]-r-4H-1,2,4-triazole;-   3-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;-   3-{4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]oct-1-yl}-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;-   4-methyl-3-{4-[4-(methylsulfonyl)phenyl]bicyclo[2.2.2]oct-1-yl}-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;-   3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-5-(3,3,3-trifluoropropyl)-1,2,4-oxadiazole;-   3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-5-(3,3,3-trifluoroethyl)-1,2,4-oxadiazole;-   5-(3,3-difluorocyclobutyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole;-   5-(1-fluoro-1-methylethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo    [2.2.2]oct-1-yl)-1,2,4-oxadiazole;-   2-(1,1-difluoroethyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole;-   2-(3,3-difluorocyclobutyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole;    and-   5-(1,1-difluoroethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole;    and    pharmaceutically acceptable salts thereof.

Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used incombination with the compounds of Formula I include, but are not limitedto:

and pharmaceutically acceptable salts thereof.

AMP-activated Protein Kinase (AMPK) activators that can be used incombination with the compounds of Formula I include, but are not limitedto:

and pharmaceutically acceptable salts thereof.

Inhibitors of acetyl-CoA carboxylase-1 and 2 (ACC-1 and ACC-2) that canbe used in combination with the compounds of Formula I include, but arenot limited to:

-   3-{1′-[(1-cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}benzoic    acid;-   5-{1′-[(1-cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic    acid;-   1′-[(1-cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;-   1′-[(1-cyclopropyl-4-ethoxy-3-methyl-1H-indol-6-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;-   5-{1′-[(1-cyclopropyl-4-methoxy-3-methyl-1H-indol-6-yl)carbonyl]-4-oxo-spiro[chroman-2,4′-piperidin]-6-yl}nicotinic    acid;-   4)-({6-(5-carbamoylpyridin-2-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl}carbonyl)-2′,6′-diethoxydiphenyl-4-carboxylic    acid;-   2′,6′-diethoxy-4′-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}biphenyl-4-carboxylic    acid;-   2′,6′-diethoxy-3-fluoro-4′-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}biphenyl-4-carboxylic    acid;-   5-[4-({6-(3-carbamoylphenyl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl}carbonyl)-2,6-diethoxyphenyl]nicotinic    acid;-   sodium    4′-({6-(5-carbamoylpyridin-2-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl}carbonyl)-2′,6′-diethoxybiphenyl-4-carboxylate;-   methyl    4′-({6-(5-carbamoylpyridin-2-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl}carbonyl)-2′,6′-diethoxybiphenyl-4-carboxylate;-   1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;-   (5-{1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}-2H-tetrazol-2-yl)methyl    pivalate;-   5-{1′-[(8-cyclopropyl-4-methoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic    acid;-   1′-(8-methoxy-4-morpholin-4-yl-2-naphthoyl)-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;    and-   1′-[(4-ethoxy-8-ethylquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;    and    pharmaceutically acceptable salts and esters thereof.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.(For purposes of this application, topical application shall includemouthwashes and gargles.)

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment or prevention of conditions which require inhibition ofdipeptidyl peptidase-IV enzyme activity an appropriate dosage level willgenerally be about 0.01 to 500 mg per kg patient body weight per daywhich can be administered in single or multiple doses. Preferably, thedosage level will be about 0.1 to about 250 mg/kg per day; morepreferably about 0.5 to about 100 mg/kg per day. A suitable dosage levelmay be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day,or about 0.1 to 50 mg/kg per day. Within this range the dosage may be0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining 1.0 to 1000 mg of the active ingredient, particularly 1.0,5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0,300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of thepresent invention are indicated, generally satisfactory results areobtained when the compounds of the present invention are administered ata daily dosage of from about 0.1 mg to about 100 mg per kilogram ofanimal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 mg to about1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70kg adult human, the total daily dose will generally be from about 7 mgto about 350 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Synthetic methods for preparing the compounds of the present inventionare illustrated in the following Schemes and Examples. Startingmaterials are commercially available or may be made according toprocedures known in the art or as illustrated herein.

The compounds of the present invention can be prepared fromintermediates such as those of formula II and III by nucleophilicdisplacement of the iodo group in the δ-lactam of formula II with anamine of formula III to generate an amino δ-lactam of formula IVfollowed by reduction of the keto group and cleavage of the amineprotecting group P to give final product V using standard methodsdescribed in T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis,” 4^(th) Ed., John Wiley & Sons, Inc., 2007,

wherein Ar, V, and R^(a) are as defined above and P is a suitablenitrogen protecting group such as tert-butoxycarbonyl (BOC),benzyloxycarbonyl (Cbz), or 9-fluorenylmethoxycarbonyl (Fmoc). Thepreparation of these intermediates is described in the followingSchemes.

Intermediates of formula 18 may be conveniently prepared as shown inScheme 1.

5-Nitro-piperidinone 13 can be prepared by condensing an appropriatelysubstituted benzaldehyde with methyl 4-nitrobutyrate in the presence ofa source of ammonia such as ammonium acetate in refluxing ethanol. Theresulting racemic trans isomer 13 is then separated by chiralchromatography to provide the desired enantiomer 14. Reduction of 14with sodium borohydride in the presence of nickel(II) chloride inmethanol and usual workup gives a primary amine which can be protectedwith various known amine protecting groups. Iodoination of 15 can becarried out by treating 15 with a base such asN,N,N′,N′-tetramethylethylenediamine in the presence ofiodotrimethylsilane followed by addition of a iodinating agent such asiodine in a solvent such as dichloromethane. Treatment of the iodinatedpiperidinone intermediate 16 with various amines (represented by V-H)gives 17 after chromatographic resolution of the two resultingdiastereoisomers formed. Reduction of the protected piperidinone 17 witha reagent such as borane-methyl sulfide in a solvent such astetrahydrofuran at a temperature ranging from ambient to refluxtemperature gives the piperidine 18. Treatment of piperidine 18 with asuitable substitution reagent leads to 19 which can be deprotected toprovide the desired amino piperidine 20 by treatment with an appropriatedeprotecting agent such as hydrochloric acid or trifluoroacetic acidwhen the t-butoxycarbonyl (Boc) group is used as a protecting group P.

Intermediates of formula VI are known in the literature or may beconveniently prepared by a variety of methods familiar to those skilledin the art. One common route to prepare tetrahydropyrrolopyrazole VI isillustrated in Scheme 2. Trityl- or Boc-protected pyrrolidinol 21 may beoxidized by a variety of methods, such as the Swern procedure, commonlyknown to those in the art, to give the ketone 22, which upon treatmentand heating with N,N-dimethylformamide dimethylacetal (DMF-DMA) gives23. Intermediate 24 may then be readily obtained by heating a solutionof 23 with a hydrazine in a suitable solvent such as ethanol optionallyin the presence of a base such as sodium ethoxide. Substitution of 24may be done using the appropriate reagent. Intermediate VI is obtainedafter removal of the protecting group.

In some cases a compound of structural formula (I) or syntheticintermediates illustrated in the above schemes may be further modified,for example, by manipulation of substituents on Ar or V. Thesemanipulations may include, but are not limited to, reduction, oxidation,alkylation, acylation, and hydrolysis reactions that are commonly knownto those skilled in the art. In some cases the order of carrying out theforegoing reaction schemes may be varied to facilitate the reaction orto avoid unwanted reaction products.

The compounds of structural formula I of the present invention can beprepared according to the procedures of the following Schemes andExamples using appropriate materials and are further exemplified by thefollowing specific examples. These specific examples are provided sothat the invention might be more fully understood and are to beconsidered illustrative only and should not be construed as limiting theinvention in any way. The Examples further illustrate details for thepreparation of the compounds of the present invention. Those skilled inthe art will readily understand that known variations of the conditionsand processes of the following preparative procedures can be used toprepare these compounds. The instant compounds are generally isolated inthe form of their pharmaceutically acceptable salts, such as thosedescribed previously hereinabove. The free amine bases corresponding tothe isolated salts can be generated by neutralization with a suitablebase, such as aqueous sodium hydrogencarbonate, sodium carbonate, sodiumhydroxide, and potassium hydroxide, and extraction of the liberatedamine free base into an organic solvent followed by evaporation. Theamine free base isolated in this manner can be further converted intoanother pharmaceutically acceptable salt by dissolution in an organicsolvent followed by addition of the appropriate acid and subsequentevaporation, precipitation, or crystallization. All temperatures aredegrees Celsius unless otherwise noted. Mass spectra (MS) were measuredby electron-spray ion-mass spectroscopy.

The following is a list of abbreviations used in the description of thesynthesis of the Intermediates and Examples shown below.

List Of Abbreviations:

-   Alk=alkyl-   Ar=aryl-   Boc=tert-butoxycarbonyl-   br=broad-   CH₂Cl₂=dichloromethane-   d=doublet-   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene-   DEAD=diethyl azodicarboxylate-   DMA=N,N-dimethylacetamide-   DMF=dimethylformamide-   DMSO=dimethyl sulfoxide-   ESI=electrospray ionization-   EtOAc=ethyl acetate-   HATU=O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium    hexafluorophosphate-   HOAc=acetic acid-   LC-MS=liquid chromatography-mass spectroscopy-   LiOH=lithium hydroxide-   m=multiplet-   MeOH=methyl alcohol-   MgSO₄=magnesium sulfate-   MS=mass spectroscopy-   NaOH=sodium hydroxide-   Na₂SO₄=sodium sulfate-   NMR=nuclear magnetic resonance spectroscopy-   PG=protecting group-   Ph=phenyl-   Rt or RT=room temperature-   s=singlet-   t=triplet-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran

INTERMEDIATE 1

2-(Methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolebenzenesulfonic acid salt Step A: tert-Butyl(3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate

tert-Butyl 3-oxopyrrolidine-1-carboxylate (40 g, 216 mmol) was treatedwith N,N-dimethylformamide dimethyl acetal (267 g, 2241 mmol) and heatedat 105° C. for 40 min. The solution was cooled and evaporated underreduced pressure and the resulting orange solid was treated with hexane(200 mL) and cooled in the refrigerator for 64 h. The resultingbrownish-yellow solid obtained as such was collected by filtration,dried and used in the next step without further purification. LC/MS:241.1 (M+1).

Step B: tert-Butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate

A solution of hydrazine (3 mL) and tert-butyl(3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (19.22g) in ethanol (40 mL) was heated at 85° C. in a sealed tube for 4 h.Solvent was removed under reduced pressure, and the residue wastriturated with dichloromethane (160 mL) and ethyl acetate (15 mL). Theresulting solid was filtered. The filtrate was concentrated and theresulting solid was triturated again and filtered. The combined solidswere used without further purification. LC/MS: 210.1 (M+1).

Step C: tert-Butyl2-(methylsulfonyl)]-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate(B)

A solution of the product from Step B (100 g, 478 mmol) in anhydrousN,N-dimethylformamide (1.0 L) was cooled to −40° C. and treated with 1 Msodium bis(trimethylsilyl)amide in tetrahydrofuran (502 mL, 502 mmol)slowly over 20 min. The temperature warmed to −30° C. during theaddition and the mixture was stirred at this temperature for 1 h.Methanesulfonyl chloride (44.7 mL, 573 mmol) was slowly added viaaddition funnel and stirred for an additional 1.5 h at −30 to −40° C.The reaction mixture was quenched with ice (3.5 kg), slowly warmed toambient temperature and stirred for 48 h. The resulting white solid wasfiltered, washed with water and suction dried to afford the titlecompound. LC/MS: 288.1 (M+1).

Step D: 2-(Methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolebenzenesulfonic acid salt

To the product from Step C (87 g, 303 mmol) in isopropyl acetate (1 L)was added benzensulfonic acid (71.8 g, 454 mmol) and the mixture warmedto 40° C. and stirred for 2 h. The mixture was cooled to ambienttemperature and stirred for 16 h to give an off white slurry. The solidwas filtered, washed with isopropyl acetate, and suction dried to affordthe title compound as a white solid. LC/MS: 188.1 (M+1).

INTERMEDIATE 2

2-(Cyclopropylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoletrifluoroacetic acid salt Step A: tert-Butyl2-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate

To A suspension of sodium hydride (60% dispersion in oil, 1.55 g, 38.7mmol) in anhydrous acetonitrile (200 mL) was added to1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (Intermediate 1, Step B) (5.3g, 25.5 mmol) in one portion under nitrogen at room temperature. Thereaction mixture was stirred at room temperature for 2 h. To theresulting white suspension was slowly added cyclopropanesulfonylchloride (6.9 g, 49.1 mmol) and the mixture was stirred at roomtemperature for 18 h, quenched with water (120 mL) and the layers wereseparated. The aqueous layer was then extracted with dichloromethane(2×100 mL). The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The crude material waspurified on silica chromatography (300 g Biotage™ column) and elutedwith 15-80% ethyl acetate in hexanes to yield the title compound andtert-butyl1-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylateas a white solid. LC/MS: 314.2 (M+1).

Step B: 2-(Cyclopropylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoletrifluoroacetic acid salt

A solution of product from Step A (205 mg, 0.65 mmol) in dichloromethane(4.0 mL) was treated with trifluoroacetic acid (4.0 mL) at roomtemperature. After 1.5 h the solvent was removed in vacuo to give thetitle compound that was used without purification. ¹H NMR (500 MHz,CD₃OD): δ 1.17-1.23 (m, 2H); 1.31-1.38 (m, 2H); 2.84-2.91 (m, 1H);3.96-3.99 (m, 4H); 7.82 (s, 1H). LC/MS: 214.1 (M+1).

INTERMEDIATE 3

tert-Butyl{(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamateStep A: (5S,6R)-6-(2,5-Difluorophenyl)-5-nitropiperidin-2-one

To a solution of 2,5-difluorobenzaldehyde (3.82 mL, 35.2 mmol) inethanol (70 mL) was added methyl 4-nitrobutyrate (4.51 mL, 35.2 mmol)and the mixture was stirred for 5 minutes. To the reaction mixture wasadded ammonium acetate (5.42 g, 70.4 mmol) and the mixture stirred for10 minutes at ambient temperature and then heated at reflux temperaturefor 16 h. The solvent was removed in vacuo and to the yellow oil wasadded saturated aqueous sodium hydrogen carbonate (100 mL) and theaqueous phase extracted with ethyl acetate (3×50 mL). The combinedorganic phases were washed with saturated aqueous brine (1×50 mL), driedwith anhydrous sodium sulfate, filtered and the solvent removed invacuo. The yellow racemic product was purified by preparative HPLC on aBerger SFC using ChiralPak AS-H™ column, eluting with 20% MeOH/CO₂ togive (5R,6S)-6-(2,5-difluorophenyl)-5-nitropiperidin-2-one [LC/MS 257.1(M+1)] as the second eluting isomer and the title compound as the firsteluting isomer. LC/MS 257.1 (M+1).

Step B:tert-Butyl[(2R,3S)-2-(2,5-difluorophenyl)-6-oxopiperidin-3-yl]carbamate

To a solution of product from step A (9.02 g, 35.2 mmol) in methanol(175 mL) at 0° C. was added nickel(II) chloride hexahydrate (0.418 g,1.76 mmol) and the mixture was stirred for 5 min. To the mixture wasadded sodium borohydride (5.33 g, 141 mmol) in five portions over 30min. The mixture was stirred for an additional 30 min at 0° C. and thendi-tert-butyl dicarbonate (9.22 g, 42.2 mmol) was added and the mixtureslowly warmed to ambient temperature over 1 h. After stirring for anadditional 14 h the mixture was poured into a 2:1 mixture of saturatedaqueous brine and saturated aqueous sodium hydrogen carbonate (200 mL)and ethyl acetate (200 mL). The aqueous layer was separated andextracted with ethyl acetate (4×50 mL). The combined organic phases werewashed with saturated aqueous brine (1×50 mL), dried with anhydroussodium sulfate, filtered and the solvent removed in vacuo. The whitesolid was diluted with ethyl acetate and triturated with hexanes toafford the title compound after filtration. LC/MS 327.1 (M+1).

Step C:tert-Butyl[(2R,3S)-2-(2,5-difluorophenyl)-5-iodo-6-oxopiperidin-3-yl]carbamate

To a solution of the product from Step B (2 g, 6.13 mmol) indichloromethane (50 mL) at 0° C. was addedN,N,N′,N′-tetramethylethylenediamine (4.62 mL, 30.6 mmol) followed byslow addition of iodotrimethylsilane (2.59 mL, 19.0 mmol). The yellowmixture was stirred for 2 h at 0° C. and iodine (3.11 g, 12.26 mmol) wasadded in one portion. The mixture was stirred for 3 h at ° C. andsaturated aqueous sodium thiosulfate (50 mL) added. The mixture wasstirred for 10 min, the layers were separated and the aqueous phaseextracted with dichloromethane (3×25 mL) and the combined organic phasesdried with anhydrous sodium sulfate, filtered and the solvent removed invacuo. The crude yellow solid was purified by column chromatography(silica gel Biotage 40S) eluting with ethyl acetate/hexane (gradientfrom 0% to 100%) to give the title compound as a colorless solid. LC/MS453.2 (M+1).

Step D:tert-Butyl{(2R,3S)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-6-oxopiperidin-3-yl}carbamate

To a solution of product from Step C (30.0 g, 66.3 mmol) andIntermediate 1 (25.2 g, 73.0 mmol) in dichloromethane (400 mL) andN,N-dimethylformamide (20 mL) was addedN,N,N′,N′-tetramethylethylenediamine (35.0 mL, 232 mmol) over 10 min.The mixture was warmed to ambient temperature over 30 min and stirringcontinued for 64 h. Saturated aqueous sodium hydrogen carbonate solution(200 mL) was added. The mixture was stirred for 10 min, the layers wereseparated and the aqueous phase extracted with dichloromethane (3×100mL) and the combined organic phases were dried with anhydrous sodiumsulfate, filtered and the solvent removed in vacuo. The crude solid waspurified by column chromatography (silica gel 3× Biotage 65i) elutingwith ethyl acetate/hexane (gradient from 0% to 100%) to give the titlecompound as a colorless solid. LC/MS 512.2 (M+1).

Step E:tert-Butyl{(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate

To a solution of the product from Step D (18.43 g, 36.0 mmol) intetrahydrofuran (250 mL) was added borane dimethyl sulfide complexsolution (144 mL, 288 mmol, 2.0 M solution in tetrahydrofuran) over 15min. The reaction was placed in a preheated 70° C. bath and stirred for75 min. The mixture was cooled to 0° C. and methanol (100 mL) slowlyadded over 15 min. The ice bath was removed and the mixture stirred for30 min and the solvent removed in vacuo. The residue was dissolved inethanol (150 mL) and heated at 70° C. for 4 h, cooled to ambienttemperature and the solvent removed in vacuo. The crude solid waspurified by column chromatography (silica gel Biotage 40M) eluting withmethanol/ethyl acetate (gradient from 0% to 10%) to give the minor(first eluting) diastereomer tert-butyl{(2R,3S,5S)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamateand the major (second eluting) diastereomer, the title compound ascolorless solids. LC/MS 498.2 (M+1).

INTERMEDIATE 4

tert-Butyl{(2R,3S,5R)-2-(2,3,5-trifluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate

This intermediate was made as described for Intermediate 3 from thecorresponding 2,3,5-trifluorobenzaldehyde.

INTERMEDIATE 5

tert-Butyl{(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(cyclopropylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate

This intermediate was made as described for Intermediate 3 bysubstituting Intermediate 2 in Step D.

INTERMEDIATE 6

tert-Butyl{(2R,3S,5R)-2-(2,3,5-trifluorophenyl)-5-[2-(cyclopropylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate

This intermediate was made as described for Intermediate 3 from thecorresponding 2,3,5-trifluorobenzaldehyde and by substitutingIntermediate 2 in Step D.

INTERMEDIATE 7

2-[1-(Methylsulfonyl)-1H-pyrazol-4-yl]ethyl methanesulfonate

To 2-(1H-pyrazol-4-yl)ethanol (50 mg, 0.45 mmol) in dichloromethane (3mL) at 0° C. was added methanesulfonyl chloride (0.104 mL, 1.39 mmol)followed by N,N-diisopropylethylamine (0.312 mL, 1.78 mmol) dropwise.The ice bath was removed and the mixture warmed to ambient temperatureand stirred for 1 h. The solvent was removed in vacuo and the residuepurified by column chromatography (silica gel Biotage 25S) eluting withethyl acetate/hexane (gradient from 0% to 100%) to give the titlecompound as a colorless solid. LC/MS 269.2 (M+1).

INTERMEDIATE 8

2-(Isoxazol-4-yl)ethyl methanesulfonate

This intermediate was made as described for Intermediate 7 bysubstituting 2-(isoxazol-4-yl)ethanol.

INTERMEDIATE 9

2-(1H-Imidazol-1-yl)ethyl methanesulfonate

This intermediate was made as described for Intermediate 7 bysubstituting 2-(1H-imidazol-1-yl)ethanol.

EXAMPLE 1

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-aminetris(trifluoroacetic acid salt)

To Intermediate 3 (11 mg, 0.02 mmol) was added a 2:1 mixture ofdichloromethane and trifluoroacetic acid (0.6 mL). The mixture wasstirred for 1 h, and the solvent removed in vacuo. The residue waspurified by preparative reverse phase HPLC(YMC Pro-C18 column), elutingwith acetonitrile/water containing 0.1% trifluoroacetic acid to affordthe title compound as a colorless solid. LC/MS 398.2 (M+1).

EXAMPLE 2

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)piperidin-3-aminetris(trifluoroacetic acid salt)

To Intermediate 3 (11 mg, 0.02 mmol) was added concentrated (37%)hydrochloric acid (0.5 mL). The mixture was stirred for 24 h, and thesolvent removed in vacuo. The residue was purified by preparativereverse phase HPLC(YMC Pro-C18 column), eluting with acetonitrile/watercontaining 0.1% trifluoroacetic acid to afford the title compound as acolorless solid. LC/MS 320.2 (M+1).

EXAMPLE 3

(2R,3S,5R)-2-(2,3,5-Trifluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-aminetris(trifluoroacetic acid salt)

To Intermediate 4 (28 mg, 0.054 mmol) was added a 2:1 mixture ofdichloromethane and trifluoroacetic acid (1.5 mL). The mixture wasstirred for 1 h, and the solvent removed in vacuo. The residue waspurified by preparative reverse phase HPLC(YMC Pro-C18 column), elutingwith acetonitrile/water containing 0.1% trifluoroacetic acid to affordthe title compound as a colorless solid. LC/MS 416.2 (M+1).

EXAMPLE 4

(2R,3S,5R)-2-(2,3,5-Trifluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)piperidin-3-aminetris(trifluoroacetic acid salt)

To Example 3 (8.0 mg, 0.01 mmol) was added concentrated (37%)hydrochloric acid (0.3 mL). The mixture was stirred for 24 h, and thesolvent removed in vacuo. The residue was purified by preparativereverse phase HPLC (YMC Pro-C18 column), eluting with acetonitrile/watercontaining 0.1% trifluoroacetic acid to afford the title compound as acolorless solid. LC/MS 338.2 (M+1).

EXAMPLE 5

2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(cyclopropylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-aminetris(trifluoroacetic acid salt)

To Intermediate 5 (150 mg, 0.286 mmol) was added a 2:1 mixture ofdichloromethane and trifluoroacetic acid (3.0 mL). The mixture wasstirred for 1.5 h, and the solvent removed in vacuo. The residue waspurified by preparative reverse phase HPLC (YMC Pro-C18 column), elutingwith acetonitrile/water containing 0.1% trifluoroacetic acid to affordthe title compound as a colorless solid. LC/MS 424.2 (M+1).

EXAMPLE 6

(2R,3S,5R)-2-(2,3,5-Trifluorophenyl)-5-[2-(cyclopropylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-aminetris(trifluoroacetic acid salt)

To Intermediate 6 (70 mg, 0.129 mmol) was added a 2:1 mixture ofdichloromethane and trifluoroacetic acid (1.5 mL). The mixture wasstirred for 1 h, and the solvent removed in vacuo. The residue waspurified by preparative reverse phase HPLC (YMC Pro-C18 column), elutingwith acetonitrile/water containing 0.1% trifluoroacetic acid to affordthe title compound as a colorless solid. LC/MS 442.2 (M+1).

EXAMPLE 7

1-{(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}ethanonebis(trifluoroacetic acid salt) Step A:tert-Butyl{(2R,3S,5R)-1-acetyl-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate

To Intermediate 3 (4 mg, 0.008 mmol) in dichloromethane (0.5 mL) wasadded N,N-diisopropylethylamine (0.003 mL, 0.016 mmol) followed byacetic acid anhydride (0.002 mL, 0.02 mmol). The mixture was stirred for5 h and placed on a preparative thin layer chromatography plate(Analtech 500 μm) and eluted with ethyl acetate to afford the titlecompound as a colorless solid. LC/MS 540.2 (M+1).

Step B:1-{(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}ethanonebis(trifluoroacetic acid salt)

To the product from Step A (3 mg, 0.006 mmol) was added a 2:1 mixture ofdichloromethane and trifluoroacetic acid (0.6 mL). The mixture wasstirred for 1 h, and the solvent removed in vacuo. The residue waspurified by preparative reverse phase HPLC (YMC Pro-C18 column), elutingwith acetonitrile/water containing 0.1% trifluoroacetic acid to affordthe title compound as a colorless solid. LC/MS 440.2 (M+1).

EXAMPLE 8

1-{(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}-2-(pyrazin-2-yl)ethanonetris(trifluoroacetic acid salt) Step A:tert-Butyl[(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-(pyrazin-2-ylacetyl)piperidin-3-yl]carbamate

To Intermediate 3 (14 mg, 0.028 mmol) and pyrazin-2-ylacetic acid (5.1mg, 0.04 mmol) in N,N-dimethylformamide (1.0 mL) was addedN,N-diisopropylethylamine (0.015 mL, 0.084 mmol) followed byO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (16.0 mg, 0.042 mmol). The mixture wasstirred for 30 min and saturated aqueous sodium hydrogen carbonate (5mL) added. The mixture was extracted with ethyl acetate (3×5 mL) and thecombined organic fractions were washed with saturated aqueous brine (1×5mL), dried over anhydrous sodium sulfate, filtered and the solventevaporated in vacuo. The crude solid was used without furtherpurification. LC/MS 618.2 (M+1).

Step B:1-{(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}-2-(pyrazin-2-yl)ethanonetris(trifluoroacetic acid salt)

To the product from Step A (10.4 mg, 0.017 mmol) was added a 2:1 mixtureof dichloromethane and trifluoroacetic acid (0.375 mL). The mixture wasstirred for 1 h, and the solvent removed in vacuo. The residue waspurified by preparative reverse phase HPLC (YMC Pro-C18 column), elutingwith acetonitrile/water containing 0.1% trifluoroacetic acid to affordthe title compound as a colorless solid. LC/MS 518.2 (M+1).

EXAMPLE 9

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-(pyridine-2-ylmethyl)piperidin-3-aminetris(trifluoroacetic acid salt) Step A:tert-Butyl[(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-(pyridine-2-ylmethyl)piperidin-3-yl]carbamate

To Intermediate 3 (35 mg, 0.07 mmol) in acetonitrile (1 mL) was added2-(brommethyl)pyridine hydrobromide salt (26.7 mg, 0.106 mmol) followedby N,N-diisopropylethylamine (0.061 mL, 0.35 mmol). The mixture wasstirred for 4 h and the solvent removed in vacuo. The residue waspurified by preparative thin layer chromatography plate (Analtech 1500μm) and eluted with 5% methanol in ethyl acetate to afford the titlecompound as a colorless solid. LC/MS 589.2 (M+1).

Step B:(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-(pyridine-2-ylmethyl)piperidin-3-aminetris trifluoroacetic acid salt)

To the product from Step A (16 mg, 0.027 mmol) was added a 2:1 mixtureof dichloromethane and trifluoroacetic acid (0.375 mL). The mixture wasstirred for 1 h, and the solvent removed in vacuo. The residue waspurified by preparative reverse phase HPLC (YMC Pro-C18 column), elutingwith acetonitrile/water containing 0.1% trifluoroacetic acid to affordthe title compound as a colorless solid. LC/MS 489.2 (M+1).

EXAMPLE 10

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5-(4H)-yl)-1-[2-H-pyrazol-4-yl)ethyl]piperidin-3-aminetris(trifluoroacetic acid salt) Step A:tert-Butyl[(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-{2-[1-methylsulfonyl)-1H-pyrazol-4-yl]ethyl}piperidin-3-yl}carbamate

Intermediate 3 (20 mg, 0.04 mmol), Intermediate 7 (54 mg, 0.201 mmol),sodium carbonate (30.0 mg, 0.28 mmol) and sodium iodide (36.2 mg, 0.24mmol) in acetonitrile (1.0 mL) were stirred at ambient temperature for 5min then heated at reflux for 18 h. The mixture was filtered, washedwith acetonitrile and the solvent removed in vacuo. The residue waspurified by preparative thin layer chromatography plate (Analtech 1500μm) and eluted with ethyl acetate to afford the title compound as acolorless solid. LC/MS 670.2 (M+1).

Step B:(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-1-[2-(1H-pyrazol-4-yl)ethyl]piperidin-3-aminetris(trifluoroacetic acid salt)

To the product from Step A (25 mg, 0.037 mmol) was added concentrated(37%) hydrochloric acid (1.0 mL). The mixture was stirred for 24 h, andthe solvent removed in vacuo. The residue was purified by preparativereverse phase HPLC (YMC Pro-C18 column), eluting with acetonitrile/watercontaining 0.1% trifluoroacetic acid to afford the title compound as acolorless solid. LC/MS 414.2 (M+1).

EXAMPLE 11

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-(1,3-oxazol-4-ylmethyl)piperidin-3-aminetris(trifluoroacetic acid salt) Step A:tert-Butyl[(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-(1,3-oxazol-4-ylmethyl)piperidin-3-yl]carbamate

Intermediate 3 (20 mg, 0.04 mmol) and 1,3-oxazole-4-carbaldehyde (6.5mg, 0.06 mmol) in N,N-dimethylacetamide (0.5 mL) were stirred for 5 minand acetic acid (0.007 mL, 0.08 mmol) was added. The mixture was stirredfor 4 h and sodium triacetoxyborohydride (17 mg, 0.08 mmol) was added inone portion. The mixture was stirred for 18 h, quenched with methanol(0.5 mL) and purified by preparative reverse phase HPLC (YMC Pro-C18column), eluting with acetonitrile/water containing 0.1% trifluoroaceticacid to afford the title compound as a colorless solid. LC/MS 579.2(M+1).

Step B:2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-(1,3-oxazol-4-ylmethyl)piperidin-3-aminetris(trifluoroacetic acid salt)

To the product from Step A (30 mg, 0.037 mmol) was added a 2:1 mixtureof dichloromethane and trifluoroacetic acid (0.375 mL). The mixture wasstirred for 1 h, and the solvent removed in vacuo. The residue waspurified by preparative reverse phase HPLC (YMC Pro-C18 column), elutingwith acetonitrile/water containing 0.1% trifluoroacetic acid to affordthe title compound as a colorless solid. LC/MS 479.2 (M+1).

EXAMPLE 12

(2S)-1-{(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}propan-2-olStep A:tert-Butyl{(2R,3S,5R)-2-(2,5-difluorophenyl)-1-[(2S)-2-hydroxypropyl]-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate

To Intermediate 3 (100 mg, 0.2 mmol) in dichloromethane (0.7 mL) andmethanol (0.7 mL) was added (R)-(+)-propylene oxide (94 mg, 1.608 mmol).The mixture was heated at 55° C. for 3 days, the solvent was removed invacuo and the residue was purified by preparative thin layerchromatography (Analtech 1500 μm) and eluted with methanol containing10% ammonium hydroxide in dichloromethane (7:93) to afford the titlecompound as a colorless solid. LC/MS 556.2 (M+1).

Step B:(2S)-1-{(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}propan-2-ol

To the product from Step A (18 mg, 0.032 mmol) was added a 1:1 mixtureof dichloromethane and trifluoroacetic acid (0.5 mL). The mixture wasstirred for 1 h, and the solvent removed in vacuo. The residue waspurified by preparative thin layer chromatography (Analtech 1000 μm) andeluted with methanol containing 10% ammonium hydroxide indichloromethane (10:90) to afford the title compound as a colorlesssolid. LC/MS 456.2 (M+1).

EXAMPLE 13

(2S)-1-[(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl]propan-2-ol

To the product from Example 12 Step A (57 mg, 0.103 mmol) was addedconcentrated (37%) hydrochloric acid (0.5 mL) The mixture was stirredfor 5 h, and the solvent removed in vacuo. The residue was purified bypreparative thin layer chromatography (Analtech 1000 μm) and eluted withmethanol containing 10% ammonium hydroxide in dichloromethane (7:93) toafford the title compound as a colorless solid. LC/MS 378.2 (M+1).

EXAMPLE 14

(2R,3S,5R)-2-(2,5-Difluorophenyl)-1-[(2R)-2-fluoropropyl]-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-aminetris(trifluoroacetic acid salt) Step A:tert-Butyl{(2R,3S,5R)-2-(2,5-difluorophenyl)-1-[(2R)-2-fluoropropyl]-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamatebis(trifluoroacetic acid salt)

To the product of Example 12 Step A (40 mg, 0.072 mmol) indichloromethane (0.5 mL) was slowly added (diethylamino)sulfurtrifluoride (0.02 mL, 0.144 mmol) at −78° C. The mixture was slowlywarmed to ambient temperature over 1 h and stirred for 2 h. The solventremoved in vacuo the residue was purified by preparative reverse phaseHPLC (YMC Pro-C18 column), eluting with acetonitrile/water containing0.1% trifluoroacetic acid to afford the title compound as a colorlesssolid. LC/MS 558.2 (M+1).

Step B:(2R,3S,5R)-2-(2,5-Difluorophenyl)-1-[(2R)-2-fluoropropyl]-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-aminetris(trifluoroacetic acid salt)

To the product from Step A (61 mg, 0.078 mmol) was added concentrated(37%) hydrochloric acid (0.3 mL). The mixture was stirred for 50 min,and the solvent removed in vacuo. The residue was purified bypreparative reverse phase HPLC (YMC Pro-C18 column), eluting withacetonitrile/water containing 0.1% trifluoroacetic acid to afford thetitle compound [LC/MS 458.2 (M+1)] and(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-1-[(2R)-2-fluoropropyl]piperidin-3-aminetris(trifluoroacetic acid salt) (Example 26) [LC/MS 380.2 (M+1)] ascolorless solids.

EXAMPLE 15

(2R,3S,5R)-2-(2,5-Difluorophenyl)-1-(2,2-fluoropropyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-aminetris(trifluoroacetic acid salt) Step A:tert-Butyl[(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-(2-oxopropyl)piperidin-3-yl]carbamate

To Intermediate 3 (100 mg, 0.2 mmol) in acetonitrile (1.0 mL) was addedN,N-diisopropylethylamine (0.105 mL, 0.603 mmol) followed bychloroacetone (38.7 mg, 0.402 mmol) and sodium iodide (60.3 mg, 0.402mmol). The mixture was stirred for 7 days, the solvent was removed invacuo and the residue was purified by preparative reverse phase HPLC(YMC Pro-C18 column), eluting with acetonitrile/water containing 0.1%trifluoroacetic acid. The compound was then desalted (Varian MEGABE-SCX, 2GM column) to afford the title compound as a colorless solid.LC/MS 554.2 (M+1).

Step B:tert-Butyl{(2R,3S,5R)-2-(2,5-difluorophenyl)-1-(2,2-difluoropropyl)-5-[2-(methylsulfonyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate

To the product of Step A (51.7 mg, 0.093 mmol) in dichloromethane (0.5mL) was slowly added (diethylamino)sulfur trifluoride (0.65 mL, 4.67mmol) at −78° C. The mixture was slowly warmed to ambient temperatureover 1 h and stirred for 2 h. The solvent was removed in vacuo and theresidue purified by preparative thin layer chromatography (Analtech 1500μm) and eluted with methanol containing 10% ammonium hydroxide indichloromethane (7:93) to afford the title compound as a colorlesssolid. LC/MS 576.2 (M+1).

Step C:(2R,3S,5R)-2-(2,5-Difluorophenyl)-1-(2,2-fluoropropyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-aminetris(trifluoroacetic acid salt)

To the product from Step B (30 mg, 0.052 mmol) was added concentrated(37%) hydrochloric acid (0.3 mL). The mixture was stirred for 50 min,and the solvent removed in vacuo. The residue was purified bypreparative reverse phase HPLC (YMC Pro-C18 column), eluting withacetonitrile/water containing 0.1% trifluoroacetic acid to afford thetitle compound [LC/MS 476.3 (M+1)] and(2R,3S,5R)-2-(2,5-difluorophenyl)-1-(2,2-difluoropropyl)-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)piperidin-3-aminetris(trifluoroacetic acid salt) (Example 27) [LC/MS 398.3 (M+1)] ascolorless solids.

EXAMPLE 16

2-{(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}acetamidetris(trifluoroacetic acid salt) Step A:tert-Butyl{(2R,3S,5R)-1-(2-amino-2-oxoethyl)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate

To Intermediate 3 (25 mg, 0.05 mmol) in acetonitrile (0.5 mL) was addedN,N-diisopropylethylamine (0.022 mL, 0.126 mmol) followed by2-bromoacetamide (14.1 mg, 0.1 mmol) slowly. The mixture was stirred for24 h and the solvent removed in vacuo. The residue was purified bypreparative thin layer chromatography (Analtech 1000 μm) and eluted withmethanol in dichloromethane (10:90) to afford the title compound as acolorless solid. LC/MS 555.2 (M+1).

Step B:2-{(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}acetamidetris(trifluoroacetic acid salt)

To the product from Step A (15 mg, 0.027 mmol) was added a 2:1 mixtureof dichloromethane and trifluoroacetic acid (0.375 mL). The mixture wasstirred for 1 h, and the solvent removed in vacuo. The residue waspurified by preparative reverse phase HPLC (YMC Pro-C18 column), elutingwith acetonitrile/water containing 0.1% trifluoroacetic acid to affordthe title compound as a colorless solid. LC/MS 455.2 (M+1).

EXAMPLE 17

{(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}aceticacid tris(trifluoroacetic acid salty Step A:{(2R,3S,5R)-3-[(tert-Butoxycarbonyl)amino]-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}aceticacid

To Intermediate 3 (238 mg, 0.478 mmol) in acetonitrile (5.0 mL) wasadded 2-bromoacetic acid (133 mg, 0.957 mmol). The mixture was stirredfor 8 days and the solvent removed in vacuo. The residue was purified bypreparative thin layer chromatography (6 Analtech 1500 μm plates) andeluted with methanol in dichloromethane (10:90) to afford the titlecompound as a colorless solid. LC/MS 556.2 (M+1).

Step B:{(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}aceticacid tris(trifluoroacetic acid salt)

To the product from Step A (8.5 mg, 0.015 mmol) was added a 2:1 mixtureof dichloromethane and trifluoroacetic acid (0.375 mL). The mixture wasstirred for 2 h, and the solvent removed in vacuo. The residue waspurified by preparative reverse phase HPLC (YMC Pro-C18 column), elutingwith acetonitrile/water containing 0.1% trifluoroacetic acid to affordthe title compound as a colorless solid. LC/MS 456.2 (M+1).

EXAMPLE 18

2-{(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanonetris(trifluoroacetic acid salt) Step A:tert-Butyl{(2R,3S,5R)-2-(2,5-difluorophenyl)-1-{2-[(3R)-3-fluoropyrrolidin-1-yl]-2-oxoethyl}-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamatebis trifluoroacetic acid salt

To the product of Example 17 Step A (60 mg, 0.108 mmol) and(3R)-3-fluoropyrrolidine hydrochloride (20.3 mg, 0.16 mmol) inN,N-dimethylfomamide (1.0 mL) was added N,N-diisopropylethylamine (0.094mL, 0.54 mmol) followed byO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (53.4 mg, 0.14 mmol). The mixture was stirredfor 2 h and the solvent evaporated in vacuo. The residue was purified bypreparative reverse phase HPLC (YMC Pro-C18 column), eluting withacetonitrile/water containing 0.1% trifluoroacetic acid to afford thetitle compound as a colorless solid. LC/MS 627.2 (M+1).

Step B:2-{(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanonetris(trifluoroacetic acid salt)

To the product from Step A (40 mg, 0.064 mmol) was added a 2:1 mixtureof dichloromethane and trifluoroacetic acid (0.75 mL). The mixture wasstirred for 2 h, and the solvent removed in vacuo. The residue waspurified by preparative reverse phase HPLC (YMC Pro-C18 column), elutingwith acetonitrile/water containing 0.1% trifluoroacetic acid to affordthe title compound as a colorless solid. LC/MS 527.2 (M+1).

EXAMPLE 19

2-[(2R,3S,5R)-3-Amino-2-(2,5-difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl]-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanonetris(trifluoroacetic acid salt)

To the product of Example 18 Step A (18.7 mg, 0.022 mmol) was addedconcentrated (37%) hydrochloric acid (0.3 mL). The mixture was stirredfor 1 h, and the solvent removed in vacuo. The residue was purified bypreparative reverse phase HPLC (YMC Pro-C18 column), eluting withacetonitrile/water containing 0.1% trifluoroacetic acid to afford thetitle compound as a colorless solid. LC/MS 449.2 (M+1).

EXAMPLE 20

(2R,3S,5R)-2-(2,5-Difluorophenyl)-1-{2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl}-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-amine(trifluoroaceticacid salt)

To a solution of the desalted product (Varian MEGA BE-SCX, 2GM column)from Example 18 Step A (29 mg, 0.055 mmol) in tetrahydrofuran (1 mL) wasadded borane dimethyl sulfide complex solution (0.22 mL, 0.44 mmol, 2.0M solution in tetrahydrofuran). The reaction was placed in a preheated70° C. bath and stirred for 1 h. The mixture was cooled to 0° C. andmethanol (1 mL) slowly added. The ice bath was removed and the mixturestirred for 30 min and the solvent removed in vacuo. The residue wasdissolved in ethanol (1 mL) and heated at 70° C. for 2.5 h, cooled toambient temperature and the solvent removed in vacuo. The crude residuewas treated with a 2:1 mixture of dichloromethane and trifluoroaceticacid (0.75 mL). The mixture was stirred for 1 h, and the solvent removedin vacuo. The residue was purified by preparative reverse phase HPLC(YMC Pro-C18 column), eluting with acetonitrile/water containing 0.1%trifluoroacetic acid to afford the title compound as a colorless solid.LC/MS 513.2 (M+1).

EXAMPLE 21

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-1-{2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl}-piperidin-3-amine(trifluoroaceticacid salt)

To Example 20 (13.5 mg, 0.026 mmol) was added concentrated (37%)hydrochloric acid (0.3 mL). The mixture was stirred for 2 h, and thesolvent removed in vacuo. The residue was purified by preparativereverse phase HPLC (YMC Pro-C18 column), eluting with acetonitrile/watercontaining 0.1% trifluoroacetic acid to afford the title compound as acolorless solid. LC/MS 435.2 (M+1).

EXAMPLE 22

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-1-[2,2,2-trifluoro(²H₂)ethyl]piperidin-3-aminetris(trifluoroacetic acid salt Step A:tert-Butyl[(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-(trifluoroacetyl)piperidin-3-yl]carbamate

To Intermediate 3 (150 mg, 0.3 mmol) in dichloromethane (2.0 mL) at 0°C. was added N,N-diisopropylethylamine (0.105 mL, 0.603 mmol) followedby trifluoroacetic anhydride (0.064 mL, 0.452 mmol). The mixture waswarmed to ambient temperature over 30 min and stirred for 1.5 h. Thesolvent was evaporated in vacuo, and the residue was purified bypreparative reverse phase HPLC (YMC Pro-C18 column), eluting withacetonitrile/water containing 0.1% trifluoroacetic acid. The compoundwas desalted (Varian MEGA BE-SCX, 2GM column) to afford the titlecompound as a colorless solid. LC/MS 594.2 (M+1).

Step B:(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-1-[2,2,2-trifluoro(²H₂)ethyl]piperidin-3-aminetris trifluoroacetic acid salt

To the product from Step A (30 mg, 0.051 mmol) was addedborane-d3-tetrahydrofuran complex solution (1 mL, 1 mmol, 1.0 M solutionin tetrahydrofuran). The reaction was placed in a preheated 70° C. bathand stirred for 2.5 h. The mixture was cooled to 0° C. and methanol (1mL) slowly added over 5 min. The ice bath was removed and the mixturestirred for 30 min and the solvent removed in vacuo. The residue wasdissolved in ethanol (1 mL) and heated at 70° C. for 3 h, cooled toambient temperature and stirred for 16 h. The solvent removed in vacuoand the residue treated with concentrated (37%) hydrochloric acid (0.3mL). The mixture was stirred for 4 h, and the solvent removed in vacuo.The residue was purified by preparative reverse phase HPLC (YMC Pro-C18column), eluting with acetonitrile/water containing 0.1% trifluoroaceticacid to afford the title compound as a colorless solid. LC/MS 404.2(M+1).

EXAMPLE 23

1-{5-[(3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)piperidin-3-yl]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-2-methylpropan-2-oltris(trifluoroacetic acid salt) Step A:tert-Butyl{(2R,3S,5R)-3-[(tert-butoxycarbonyl)amino]-2-(2,5-difluorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)piperidin-1-carboxylate

To Example 2 (mg, 2.0 mmol) in dichloromethane (15 mL) was addedN,N-diisopropylethylamine (1.86 mL, 10.65 mmol) followed bydi-tert-butyl dicarbonate (0.965 g, 4.42 mmol). The mixture was stirredfor 18 h, the solvent was evaporated in vacuo, and the residue waspurified by column chromatography (silica gel Biotage 40M) eluting withmethanol (containing 10% ammonium hydroxide)/dichloromethane (gradientfrom 0% to 5%) to afford the title compound as a colorless solid. LC/MS520.2 (M+1).

Step B:tert-Butyl{(2R,3S,5R)-3-[(tert-butoxycarbonyl)amino]-2-(2,5-difluorophenyl)-5-[2-(2-hydroxy-2-methylpropyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-carboxylate

To the product from Step A (300 mg, 0.577 mmol) in N,N-dimethylformamide(2.0 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (1.27 mL,1.27 mmol) as a 1 M solution in tetrahydrofuran. The mixture was stirredfor 10 min and 1,2-epoxy-2-methylpropane (187.0 mg, 2.6 mmol) was added.After 10 min at 0° C. the mixture was warmed to ambient temperature over30 min and stirred for 18 h. Water (1 mL) was added and the solvent wasevaporated in vacuo. The residue was purified by preparative reversephase HPLC (YMC Pro-C18 column), eluting with acetonitrile/watercontaining 0.1% trifluoroacetic acid. The compound was desalted (VarianMEGA BE-SCX, 2GM column) to afford a mixture of1-(2-hydroxy-2-methylpropyl and 2-(2-hydroxy-2-methylpropyl pyrazoles.The regioisomers were separated by preparative HPLC using Chiralcel AD™column, eluting with 10% isopropanol/heptane to givetert-butyl{(2R,3S,5R)-3-[(tert-butoxycarbonyl)amino]-2-(2,5-difluorophenyl)-5-[1-(2-hydroxy-2-methylpropyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-carboxylate[LC/MS 592.2 (M+1)] as the first eluting isomer and the title compoundas the second eluting isomer. LC/MS 592.2 (M+1).

Step C:1-{5-[(3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)piperidin-3-yl]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-2-methylpropan-2-oltris(trifluoroacetic acid salt)

To the second eluting isomer from Step B (42 mg, 0.071 mmol) was added a2:1 mixture of dichloromethane and trifluoroacetic acid (0.75 mL). Themixture was stirred for 1 h, and the solvent removed in vacuo. Theresidue was purified by preparative reverse phase HPLC (YMC Pro-C18column), eluting with acetonitrile/water containing 0.1% trifluoroaceticacid to afford the title compound as a colorless solid. LC/MS 392.2(M+1).

EXAMPLE 24

1-{5-[(3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)piperidin-3-yl]-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)-2-methylpropan-2-oltris(trifluoroacetic acid salt)

To the first eluting isomer from Example 23, Step B (13 mg, 0.021 mmol)was added a 2:1 mixture of dichloromethane and trifluoroacetic acid(0.75 mL). The mixture was stirred for 1 h, and the solvent removed invacuo. The residue was purified by preparative reverse phase HPLC (YMCPro-C18 column), eluting with acetonitrile/water containing 0.1%trifluoroacetic acid to afford the title compound as a colorless solid.LC/MS 392.2 (M+1).

EXAMPLE 25

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(2-fluoro-2-methylpropyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)piperidin-3-aminetris(trifluoroacetic acid salt) Step A:tert-Butyl{(2R,3S,5R)-3-[(tert-butoxycarbonyl)amino]-2-(2,5-difluorophenyl)-5-[2-(2-fluoro-2-methylpropyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-carboxylate

To the second eluting isomer from Example 23, Step B (60.7 mg, 0.103mmol) in dichloromethane (1 mL) at −78° C. was added(diethylamino)sulfur trifluoride (0.054 mL, 0.41 mmol). The mixture wasslowly warmed to ambient temperature over 1 h and stirred for 2 h. Thesolvent was removed in vacuo and the residue was purified by preparativereverse phase HPLC (YMC Pro-C18 column), eluting with acetonitrile/watercontaining 0.1% trifluoroacetic acid to afford the title compound as acolorless solid. LC/MS 594.2 (M+1).

Step B:(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(2-fluoro-2-methylpropyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)piperidin-3-aminetris(trifluoroacetic acid salt)

To the product from Step A (24 mg, 0.034 mmol) was added a 2:1 mixtureof dichloromethane and trifluoroacetic acid (0.75 mL). The mixture wasstirred for 1 h, and the solvent removed in vacuo. The residue waspurified by preparative reverse phase HPLC (YMC Pro-C18 column), elutingwith acetonitrile/water containing 0.1% trifluoroacetic acid to affordthe title compound as a colorless solid. LC/MS 394.2 (M+1).

The following additional Examples were made by essentially following themethods described for Examples 1 through 27.

TABLE 1

Example R^(a) R^(b) R^(c) LC/MS  28 H H

378.1  29 H H

378.1  30 H H —SO₂Et 412.1  31 —CH₂CH₂Ph H —SO₂Me 502.4  32 —SO₂Me H—SO₂Me 476.0  33 —CD₃ H —SO₂Me 415.2  34 —CD₃ H H 337.3  35 —CD₃ F—SO₂Me 433.3  36 —CD₃ F H 355.3  37 —CH₂CH₃ H H 348.3  38 —CH₂CF₃ H—SO₂Me 480.2  39 —CH₂CF₃ H H 402.2  40 —CH₂CF₃ H

474.1  41 —CH₂CF₃ H

476.2  42 —CH₂CF₃ H —SO₂Et 494.1  43 —CH₂CF₃ H

506.2  44 —CH₂CF₃ F H 420.3  45 —CH₂CH₂CF₃ H —SO₂Me 494.1  46 —CH₂CH₂CF₃H H 416.2  47 —CH₂CH₂CH₂CF₃ H —SO₂Me 508.2  48 —CH₂CH₂CH₂CF₃ H H 430.3 49 —C(O)CF₃ H —SO₂Me 494.1  50 —C(O)CF₃ H H 416.2  51 —CH₂CH₂CH₂CH₃ H—SO₂Me 490.3  52 —CH₂CH₂CH₂CH₃ H H 412.3  53 —CH₂CH₂OH H —SO₂Me 442.0 54 —CH₂CH₂OH H H 364.1  55 —CH₂CN H —SO₂Me 437.0  56 —CH₂CONH₂ H H377.1  57

H —SO₂Me 452.3  58

H H 374.3  59

H —SO₂Me 468.3  60

H H 390.3  61

H —SO₂Me 456.2  62

H H 378.2  63

H —SO₂Me 470.3  64

H —SO₂Me 470.3  65

H —SO₂Me 474.0  66

H H 396.1  67

H —SO₂Me 474.0  68

H H 396.1  69

H —SO₂Me 510.1  70

H —SO₂Me 510.1  71

H H 432.1  72

H —SO₂Me 524.0  73

H H 446.1  74

H —SO₂Me 524.0  75

H H 446.1  76

H —SO₂Me 500.2  77

H —SO₂Me 500.2  78

H —SO₂Me 514.3  79

H —SO₂Me 470.0  80

H H 392.1  81

H —SO₂Me 470.1  82

H —SO₂Me 476.1  83

H H 398.3  84

H —SO₂Me 476.1  85

H H 398.3  86

H —SO₂Me 458.2  87

H H 380.2  88

H —SO₂Me 512.2  89

H H 434.3  90

H —SO₂Me 512.2  91

H H 434.2  92

H —SO₂Me 540.3  93

H H 462.3  94

H —SO₂Me 497.2  95

H H 420.3  96

H —SO₂Me 531.2  97

H H 453.3  98

H —SO₂Me 585.3  99

H H 507.3 100

H —SO₂Me 533.3 101

H H 455.3 102

H —SO₂Me 548.3 103

H H 470.3 104

H —SO₂Me 615.3 105

H H 537.3 106

H —SO₂Me 576.3 107

H H 498.3 108

H —SO₂Me 548.3 109

H H 470.3 110

H —SO₂Me 616.2 111

H H 538.2 112

H —SO₂Me 616.2 113

H H 538.2 114

H —SO₂Me 511.2 115

H H 433.2 116

H —SO₂Me 469.1 117

H —SO₂Me 511.1 118

H —SO₂Me 509.2 119

H —SO₂Me 531.2 120

H —SO₂Me 513.2 121

H H 435.2 122

H —SO₂Me 545.2 123

H H 467.2 124

H —SO₂Me 599.2 125

H H 521.2 126

H —SO₂Me 547.2 127

H —SO₂Me 561.2 128

H —SO₂Me 562.1 129

H H 484.3 130

H —SO₂Me 523.2 131

H —SO₂Me 590.1 132

H H 512.1 133

H —SO₂Me 629.2 134

H H 551.2 135

H —SO₂Me 562.2 136

H H 484.2 137

H —SO₂Me 518.1 138

H H 440.1 139

H —SO₂Me 630.3 140

H H 552.3 141

H —SO₂Me 630.3 142

H H 552.3 143

H —SO₂Me 525.2 144

H H 447.2 145

H —SO₂Me 527.1 146

H H 415.3 147

H H 414.3 148

H —SO₂Me 506.2 149

H H 428.3 150

H —SO₂Me 510.2 151

H H 432.3 152

H —SO₂Me 509.3 153

H —SO₂Me 507.2 154

H H 429.3 155

H —SO₂Me 507.2 156

H H 429.3 157

H —SO₂Me 507.2 158

H H 429.3 159

H —SO₂Me 674.2 160

H H 496.3 161

H H 411.2 162

H —SO₂Me 490.2 163

H H 412.3 164

H —SO₂Me 490.2 165

H H 412.2 166

H —SO₂Me 490.2 167

H —SO₂Me 490.2 168

H —SO₂Me 479.2 169

H H 401.2 170

H H 401.2 171

H —SO₂Me 479.2 172

H —SO₂Me 540.2 173

H H 462.2 174

H —SO₂Me 539.2 175

H —SO₂Me 529.2 176

H —SO₂Me 529.1 177

H —SO₂Me 524.1 178

H —SO₂Me 559.2 179

H —SO₂Me 478.2 180

H H 400.2

TABLE 2

Example R^(a) R^(c) LC/MS 181 H

378.1 182 H

378.1 183 —CH₂CF₃

474.1 184 —CH₂CF₃

506.2

TABLE 3

Example R^(a) R^(c) LC/MS 185 H —SO₂Me 398.2 186 H

424.2 187 —CH₂CF₂CH₃ H 398.3 188 —CH₂CF₂CH₂CH₃ H 412.3 189

—SO₂Me 452.3 190 —SO₂Me —SO₂Me 476.2 191

—SO₂Me 525.2 192

—SO₂Me 479.2 193

—SO₂Me 478.2 194

—SO₂Me 479.2 195

—SO₂Me 507.2 196

—SO₂Me 540.2 197

—SO₂Me 490.2 198

—SO₂Me 479.2 199

—SO₂Me 490.2 200

—SO₂Me 510.2Example of a Pharmaceutical Formulation

As a specific embodiment of an oral pharmaceutical composition, a 100 mgpotency tablet is composed of 100 mg of any one of the Examples, 268 mgmicrocrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg ofmagnesium stearate. The active, microcrystalline cellulose, andcroscarmellose are blended first. The mixture is then lubricated bymagnesium stearate and pressed into tablets.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inresponsiveness of the mammal being treated for any of the indicationswith the compounds of the invention indicated above. The specificpharmacological responses observed may vary according to and dependingupon the particular active compounds selected or whether there arepresent pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations ordifferences in the results are contemplated in accordance with theobjects and practices of the present invention. It is intended,therefore, that the invention be defined by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

What is claimed is:
 1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein V is selectedfrom the group consisting of:

Ar is phenyl optionally substituted with one to five R¹ substituents;each R¹ is independently selected from the group consisting of: halogen,cyano, hydroxy, C₁₋₆ alkyl, optionally substituted with one to fivefluorines, and C₁₋₆ alkoxy, optionally substituted with one to fivefluorines; each R² is independently selected from the group consistingof hydrogen, halogen, cyano, and C₁₋₄ alkyl optionally substituted withone to five fluorines; R^(3a) and R^(3b) are each independently hydrogenor C₁₋₄ alkyl optionally substituted with one to five fluorines; R^(a)is selected from the group consisting of: hydrogen, —C₁₋₆ alkyl, whereinalkyl is substituted with one to five substituents independentlyselected from CO₂H, cyano, deuterium, fluorine, hydroxy, and C₁₋₄alkoxycarbonyl, —C₁₋₄ alkylcarbonyl, wherein the alkyl moiety isoptionally substituted with one to five fluorines, —C(═O)CH₂aryl,wherein aryl is optionally substituted with one to five substituentsindependently selected hydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆alkyloxycarbonyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy,wherein alkyl and alkoxy are optionally substituted with one to fivefluorines, —C(═O)CH₂heteroaryl, wherein heteroaryl is optionallysubstituted with one to five substituents independently selectedhydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₄alkylsulfonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy areoptionally substituted with one to five fluorines, (CH₂)_(n)-heteroaryl,wherein heteroaryl is pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl,2-oxo-(1H)-pyridinyl (2-hydroxy-pyridinyl), oxazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, furyl, triazinyl, thienyl, pyrimidinyl, pyrazinyl,benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl,dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl,quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl,purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl,benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl,imidazo[1,2-a]pyridinyl, [1,2,4-triazolo][4,3-a]pyridinyl,pyrazolo[1,5-a]pyridinyl, [1,2,4-triazolo][1,5-a]pyridinyl,2-oxo-1,3-benzoxazolyl,4-oxo-3H-quinazolinyl,3-oxo-[1,2,4]-triazolo[4,3-a]-2H-pyridinyl,5-oxo-[1,2,4]-4H-oxadiazolyl, 2-oxo-[1,3,4]-3H-oxadiazolyl,2-oxo-1,3-dihydro-2H-imidazolyl or 3-oxo-2,4-dihydro-3H-1,2,4-triazolyl,and wherein heteroaryl is optionally substituted with one to threesubstituents independently selected from hydroxy, halogen, cyano,pyrrolidin-1-yl, morpholin-1-yl, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl,C₁₋₄ alkylsulfonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl andalkoxy are optionally substituted with one to five fluorines,(CH₂)_(n)-N-heteroaryl, wherein heteroaryl is optionally substitutedwith one to three substituents independently selected from hydroxy,halogen, cyano, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₄ alkylsulfonyl,C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are optionallysubstituted with one to five fluorines, (CH₂)_(n)-heterocyclyl, whereinheterocyclyl is tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane,morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane,imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran,dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane,oxathiane, thiomorpholine, pyrrolidinone, oxazolidin-2-one,imidazolidine-2-one or pyridone and wherein the heterocyclyl isoptionally substituted with one to three substituents independentlyselected from oxo, hydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆alkyloxycarbonyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy,wherein alkyl and alkoxy are optionally substituted with one to fivefluorines, (CH₂)_(m)—C₃₋₆ cycloalkyl, wherein cycloalkyl is optionallysubstituted with one to three substituents independently selected fromhalogen, hydroxy, cyano, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₄alkylsulfonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy areoptionally substituted with one to five fluorines, (CH₂)_(n)—COOH,(CH₂)_(n)—COOC₁₋₆ alkyl, (CH₂)_(n)—NR⁴R⁵, (CH₂)_(n)—CONR⁴R⁵,(CH₂)_(n)—OCONR⁴R⁵, (CH₂)_(m)—SO₂NR⁴R⁵, (CH₂)_(n)—SO₂R⁶,(CH₂)_(n)—NR⁷SO₂R⁶, (CH₂)_(n)—NR⁷CONR⁴R⁵, (CH₂)_(n)—NR⁷COR⁷, and(CH₂)_(n)—NR⁷CO₂R⁶; wherein any individual methylene (CH₂) carbon atomin (CH₂)_(n) is optionally substituted with one to two substituentsindependently selected from fluorine, hydroxy, C₁₋₄ alkyl, and C₁₋₄alkoxy, wherein alkyl and alkoxy are optionally substituted with one tofive fluorines; R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, (CH₂)_(m)-phenyl, (CH₂)_(m)-heteroaryl, whereinthe heteroaryl is pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl,2-oxo-(1H)-pyridinyl (2-hydroxy-pyridinyl), oxazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, furyl, triazinyl, thienyl, pyrimidinyl, pyrazinyl,benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl,dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl,quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl,purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl,benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl,imidazo[1,2-a]pyridinyl, [1,2,4-triazolo][4,3-a]pyridinyl,pyrazolo[1,5-a]pyridinyl, [1,2,4-triazolo][1,5-a]pyridinyl,2-oxo-1,3-benzoxazolyl, 4-oxo-3H-quinazolinyl,3-oxo-[1,2,4]-triazolo[4,3-a]-2H-pyridinyl,5-oxo-[1,2,4]-4H-oxadiazolyl, 2-oxo-[1,3,4]-3H-oxadiazolyl,2-oxo-1,3-dihydro-2H-imidazolyl or 3-oxo-2,4-dihydro-3H-1,2,4-triazolyl,(CH₂)_(m)-heterocyclyl wherein the heterocyclyl is tetrahydrofuran(THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine,piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline,pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane,1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, pyrrolidinone,oxazolidin-2-one, imidazolidine-2-one or pyridone, (CH₂)_(m)-C₃₋₆cycloalkyl, and C₁₋₆ alkyl, wherein alkyl is optionally substituted withone to five substituents independently selected from fluorine andhydroxy and wherein phenyl, heteroaryl, heterocyclyl, and cycloalkyl areoptionally substituted with one to five substituents independentlyselected from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, whereinalkyl and alkoxy are optionally substituted with one to five fluorines;or R⁴ and R⁵ together with the nitrogen atom to which they are attachedform a heterocyclic ring selected from azetidine, pyrrolidine,piperidine, piperazine, and morpholine wherein said heterocyclic ring isoptionally substituted with one to three substituents independentlyselected from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, whereinalkyl and alkoxy are optionally substituted with one to five fluorines;and wherein said heterocyclic ring is optionally fused with a five orsix-membered heteroaryl group containing one to three heteroatomsselected from oxygen, sulfur, and nitrogen, said fused heterocyclic ringbeing optionally substituted with one to two substituents independentlyselected from halogen and C₁₋₄ alkyl optionally substituted with one tofive fluorines; R⁸ is selected from the group consisting of: hydrogen,C₁₋₆ alkyl, wherein alkyl is optionally substituted with hydroxy or oneto five fluorines, (CH₂)_(p)-phenyl, wherein phenyl is optionallysubstituted with one to five substituents independently selected fromhalogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxyare optionally substituted with one to five fluorines, (CH₂)_(p)-C₃₋₆cycloalkyl, wherein cycloalkyl is optionally substituted with one tofive substituents independently selected from halogen, hydroxy, C₁₋₆alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are optionallysubstituted with one to five fluorines, —SO₂C₁₋₆ alkyl, —SO₂C₃₋₆cycloalkyl, —SO₂-aryl, —SO₂-heteroaryl, —C(O)C₁₋₆ alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)OC₁₋₆ alkyl, —C(O)OC₃₋₆cycloalkyl, —C(O)O-aryl, —C(O)O-heteroaryl, —C(O)NHC₁₋₆ alkyl,—C(O)NHC₃₋₆ cycloalkyl, —C(O)NH-aryl, and —C(O)NH-heteroaryl; whereinalkyl and cycloalkyl are optionally substituted with one to fivefluorines and wherein aryl and heteroaryl are optionally substitutedwith one to five substituents independently selected from the groupconsisting of hydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxyare optionally substituted with one to five fluorines; each R⁶ isindependently C₁₋₆ alkyl, wherein alkyl is optionally substituted withone to five substituents independently selected from fluorine andhydroxyl; R⁷ is hydrogen or R⁶; p is an integer selected from 0 and 1;each n is an integer independently selected from 1, 2 and 3; and each mis an integer independently selected from 0, 1, and
 2. 2. The compoundof claim 1 wherein Ar is optionally substituted with one to threesubstituents independently selected from the group consisting offluorine, chlorine, bromine, methyl, trifluoromethyl, andtrifluoromethoxy.
 3. The compound of claim 2 wherein Ar is2,5-difluorophenyl or 2,4,5-trifluorophenyl.
 4. The compound of claim 1wherein R^(3a) and R^(3b) are both hydrogen.
 5. The compound of claim 1wherein V is selected from the group consisting of:


6. The compound of claim 5 wherein R² is hydrogen.
 7. The compound ofclaim 5 wherein V is


8. The compound of claim 7 wherein R² is hydrogen.
 9. The compound ofclaim 1 wherein R⁸ is selected from the group consisting of: hydrogen,C₁₋₆ alkyl, wherein alkyl is optionally substituted with hydroxy or oneto five fluorines, —SO₂C₁₋₆ alkyl, and —SO₂C₃₋₆ cycloalkyl, whereinalkyl and cycloalkyl are optionally substituted with one to fivefluorines.
 10. The compound of claim 9 wherein R⁸ is selected from thegroup consisting of hydrogen, —SO₂C₁₋₃ alkyl, and —SO₂cyclopropyl. 11.The compound of claim 1 of structural formula Ia or Ib having theindicated stereochemical configuration at the two stereogenic carbonatoms marked with an *;


12. The compound of claim 11 of structural formula Ia having theindicated absolute stereochemical configuration at the two stereogeniccarbon atoms marked with an *:


13. The compound of claim 11 of structural formulae Ic and Id having theindicated stereochemical configuration at the three stereogenic carbonatoms marked with an *:


14. The compound of claim 13 of structural formula Ic having theindicated absolute stereochemical configuration at the three stereogeniccarbon atoms marked with an *:


15. The compound of claim 14 wherein V is selected from the groupconsisting of:


16. The compound of claim 15 wherein R² is hydrogen, and R⁸ is selectedfrom the group consisting of hydrogen, —SO₂C₁₋₃ alkyl, and—SO₂cyclopropyl.
 17. The compound of claim 11 of structural formulae Ieand If having the indicated stereochemical configuration at the threestereogenic carbon atoms marked with an *:


18. The compound of claim 17 of structural formula Ie having theindicated absolute stereochemical configuration at the three stereogeniccarbon atoms marked with an *:


19. The compound of claim 18 wherein V is selected from the groupconsisting of:


20. The compound of claim 19 wherein R² is hydrogen, and R⁸ is selectedfrom the group consisting of hydrogen, —SO₂C₁₋₃ alkyl, and—SO₂cyclopropyl.
 21. The compound of claim 1 wherein each R² isindependently selected from the group consisting of hydrogen; cyano;C₁₋₆ alkyl, wherein alkyl is optionally substituted with hydroxy or oneto five fluorines; and C₃₋₆ cycloalkyl, wherein cycloalkyl is optionallysubstituted with one to three substituents independently selected fromhalogen, hydroxy, C₁₋₄ alkyl, and C₁₋₄ alkoxy, wherein alkyl and alkoxyare optionally substituted with one to five fluorines.
 22. The compoundof claim 21 wherein each R² is hydrogen.
 23. A pharmaceuticalcomposition which comprises a compound of claim 1 and a pharmaceuticallyacceptable carrier.